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mr peabody

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Aaron Byrd, Ross Buchan and Amanda Warner in the lab.

Speeding up treatments for ALS

by Mikayla MacE, University of Arizona | Medical Xpress | 11 Feb 2020

A therapeutic intervention for amyotrophic lateral sclerosis, better known as ALS or Lou Gehrig's disease, could be on the horizon thanks to unexpected findings by University of Arizona researchers.

ALS is the progressive degeneration of motor neurons that causes people to lose the ability to move and eventually speak, eat and breathe.

Within the neuronal cells of patients with ALS and other neurodegenerative diseases, two proteins—TDP-43 and FUS—are often found in bundles of molecular junk called aggregates, which can accumulate to deadly levels.

"It's not clear yet if TDP-43 aggregates themselves are truly toxic or a sign that things have gotten really bad in a cell, and this is its last Hail Mary trying to keep things in order," said Ross Buchan, assistant professor of molecular and cellular biology and a member of the BIO5 Institute. "These aggregates could possibly be toxic because they are trapping other useful molecules and not letting them do their job."

Buchan and his team set out to investigate how healthy cells clear harmful aggregates from the cell.

What they found was that the aggregates were being removed via endocytosis, which was surprising for two reasons. First, the textbook definition of endocytosis is a process in which proteins, nutrients and chemical signals from outside the cell are brought inside to be degraded and recycled by the lysosome. But in this case, endocytosis was working on aggregates that were already inside the cell. And second, there's already a mechanism, called autophagy, in place for recycling junk that originated from within a cell, yet endocytosis was doing what autophagy should have been doing instead.

"Autophagy—and also likely, although it's still uncertain, endocytosis—often slows as we age, and there are genes that are mutated in that pathway that are associated with some neurodegenerative diseases. So people thought the reason aggregates form when we get old, or when you have these diseases, is because that pathway isn't working very well," Buchan said.

Additionally, the accumulation of aggregates slows the endocytosis pathway further, creating a negative feedback loop within the cell.

"If we genetically or chemically impede the pathway, then the TDP-43 protein accumulates and becomes super toxic. The cool thing, as far as a therapy for ALS is concerned, is that we can also do the reverse," Buchan said. "We can make the endocytosis pathway work better by over-expressing parts of it, like putting the gas pedal down so it goes really fast. When we do that, then the TDP-43 aggregates are cleared really efficiently and it's no longer toxic."

Many of the paper's experiments were performed in yeast cells, but the general findings are likely translatable to human cells based on initial findings. Buchan called yeast "a powerful genetic tool for understanding cellular processes, including those in human disease."

"If I were to pull a textbook off the self, it would say endocytosis is for things that are outside the cell, not inside, so it's still pretty heretical. There are other labs with data suggesting endocytosis can also clear already internalized proteins,”
he said.

The next step is to determine how TPD-43 and FUS enter the endocytic pathway, and then to develop ways to make endocytosis work better in these cells.

"There are genetic ways to do that, but not chemically at the moment," Buchan said. "We think if we have a drug that inhibits the negative regulators of endocytosis, the pathway will go faster as a result. We have a couple ideas of where to start next."

 
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Novel gene therapy could prevent and treat ALS

Novel gene therapy could prevent and treat ALS

UC San Diego | Nature Medicine | 2 Jan 2020

This therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS.”

A new study, published in the journal Nature Medicine, has found that a new way of delivering a gene therapy could prevent and treat amyotrophic lateral sclerosis (ALS).

The study, conducted on mice, discovered that the therapy led to long-term suppression of ALS if it was given before the condition started.

Researchers from the University of California San Diego School of Medicine published the study describing how a new way of delivering a gene-silencing vector in mice could prevent and treat ALS.

Also called Lou Gehrig’s disease, ALS is a neurodegenerative disease that affects neurons (nerve cells) in the brain and spinal cord.

More than 5,000 Americans are diagnosed with ALS each year, with over 30,000 people living with the condition. Unfortunately, there is no cure for the condition; however, it is treated symptomatically. Most patients with ALS die within two to five years of diagnosis.

Senior study author Prof. Martin Marsala said, “At present, this therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS.”

In addition, effective spinal cord delivery of AAV9 vector in adult animals suggests that the use of this new delivery method will likely be effective in treatment of other hereditary forms of ALS or other spinal neurodegenerative disorders that require spinal parenchymal delivery of therapeutic gene(s) or mutated-gene silencing machinery, such as in C9orf72 gene mutation-linked ALS or in some forms of lysosomal storage disease,” he added.

Typically, ALS appears in two forms – sporadic and familial. Sporadic ALS is responsible for 90 to 95 percent of all cases, while familial ALS up to 5 to 10 percent of all cases in the United States.

Previous studies have found that nearly 200 mutations of the SOD1 gene are associated with ALS.

The SOD1 gene provides instructions for superoxide dismutase, an enzyme that breaks down toxic oxygen molecules called superoxide radicals, which are a byproduct of cellular processes. Mutations in this gene affect the removal of superoxide radicals, causing toxicity and leading to the death of neurons.

In the new study, researchers injected a harmless adeno-associated virus (AAV) carrying an artificial RNA molecule called shRNA in the spinal cord of mice just before the onset of ALS. They believe that shRNA may stop the mutation of the SOD1 gene. Marsala said, “While no detectable side effects related to treatment were seen in mice more than one year after treatment, the definition of safety in large animal specimens more similar to humans is a critical step in advancing this treatment approach toward clinical testing.”

 
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Amino acid L-Serine may be useful in treating ALS

by Brain Chemistry Labs | Medical Xpress | 20 Feb 2020

A naturally occurring amino acid is gaining increased attention from scientists as a possible treatment for ALS following a new study published today in the Journal of Neuropathology & Experimental Neurology. The study showed that the amino acid, L-serine, successfully reduced ALS-like changes in an animal model of ALS.

The scientists conducted the monkey study at the Behavioural Science Foundation, a specialized research facility on the Caribbean island of St. Kitts. After being exposed to a cyanobacterial neurotoxin called BMAA, the monkeys developed aggregations of misfolded proteins similar to those seen in human ALS patients, and activated microglia, a type of immune cells, in their spinal cord and brain, similar to those that occur in the early stages of ALS. In contrast, monkeys that also received the amino acid L-serine had significantly reduced ALS pathology.

Dr. David Davis at the Department of Neurology, University of Miami Miller School of Medicine who served as first author on the paper, said that the differences were profound. "Without L-serine co-administration, the BMAA-exposed monkeys developed motor neuron degeneration, pro-inflammatory microglia and dense inclusions of TDP-43 and other misfolded proteins known to be associated with ALS," Dr. Davis explained. "In animals dosed with L-serine, the progression of these ALS-like changes was considerably reduced."

ALS is a devastating disease that hits people in the prime of life, causing increasing paralysis and often results in death within two to three years after diagnosis. At present, only two drugs are available that slow the disease modestly. This study offers the possibility that L-serine may slow the progression of the disease even more.

Potential implications for L-Serine as a treatment

Neurobiologist Dr. Deborah Mash of Nova Southeastern University, who was also an author on the study, said that the results "holds promise for identifying a cause of sporadic ALS, which accounts for 90 percent of all ALS cases."

Dr. Elijah Stommel, a Professor of Neurology at Dartmouth Medical School, who was not associated with the study, said that these experimental results are encouraging. Stommel is conducting a Phase II trial of L-serine in 50 ALS patients. "We are attempting to replicate a previous positive trial of L-serine for ALS patients, but won't know the results until the trial is finished," he said.

L-serine is one of the twenty amino acids that make up human proteins. L-serine molecules in proteins are often the site where proteins are phosphorylated, or charged, so they can be properly folded. "Think of a charging port for an electric car," explained Dr. Paul Alan Cox, Executive Director of the Brain Chemistry Labs in Jackson Hole, "If the cable can't be connected there, the car can't be charged." Scientists at the Brain Chemistry Labs have also discovered that L-serine modulates the unfolded protein response which helps protect neurons from the damage produced by misfolded proteins.

"While these data provide valuable insights, we do not yet know if L-serine will improve outcomes for human patients with ALS," cautioned internationally renowned ALS expert, Dr. Walter Bradley, who was also an author on the study. "We need to carefully continue FDA-approved clinical trials before we can recommend that L-serine be added to the neurologists' toolbox for the treatment of ALS. However, this monkey BMAA model will be an important new tool in the quest for new drugs to treat ALS."

Dr. Larry Brand, a prominent oceanographer unassociated with the study, said that there are even broader implications of the study for human health. "These monkeys were exposed to the same cyanobacterial toxin that was found in the brains of beached dolphins with Alzheimer's neuropathology," he said. "This is one more indication that we need to carefully monitor the health effects of exposure to cyanobacterial blooms."

 
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University of Illinois at Urbana-Champaign

ALS symptoms improve with CRISPR base editing

by Abby Olena | The Scientist | 10 April 2020

Researchers slowed disease progression in the mice by injecting two different viral vectors, each containing one part of the DNA encoding the Cas9 protein, to edit the causative gene.

Base editors, which convert one nucleotide to another without a double-strand DNA break, have the potential to treat diseases caused by mutant genes. One drawback, though, is that the DNA that encodes CRISPR base editors is long—too long to fit in the adeno-associated viruses (AAVs) most commonly used for gene therapy. In a study published in Molecular Therapy on January 13, researchers split the DNA encoding a base editor into two AAV vectors and injected them into a mouse model of inherited amyotrophic lateral sclerosis (ALS). The strategy disabled the disease-causing gene, improving the animals’ symptoms and prolonging their lives.

“We’d like to be able to make gene editing tools that can fit inside an AAV vector. Unfortunately, some of the tools are so big that they can’t fit inside, so in this study, they were able to come up with a solution to that by using a split protein,” says David Segal, a biochemist at the University of California, Davis, who was not involved in the work. “It’s not the first time that that system has been used, but it’s the first time it’s been applied to this kind of base editor.”

Pablo Perez-Pinera, a bioengineer at University of Illinois at Urbana-Champaign, and colleagues developed a strategy to split the base editor into two chunks. In a study published in 2019, they generated two different AAV vectors, each containing a portion of coding DNA for an adenine-to-thymine base editor. They also included sequences encoding so-called inteins—short peptides that when they are expressed within proteins stick together and cleave themselves out, a bit like introns in RNA. The researchers built the inteins into the vectors such that when the inteins produced by the two vectors dimerized, bringing the two base editor parts together, and then excised themselves, they left behind a full-length, functional base editor.

When Perez-Pinera told Thomas Gaj, also a bioengineer at the University of Illinois at Urbana-Champaign, about the strategy, Gaj tells The Scientist, they immediately set out to test it in a mouse model of ALS. The transgenic mice have about 25 copies of the human gene, superoxide dismutase 1 (SOD1), with mutations that cause ALS in people. The animals display motor neuron loss and muscle atrophy, plus their neurons accumulate inclusions—dense spots in the gray and white matter of their spinal cords that include SOD1 protein—before dying at about four months of age on average. The symptoms and life expectancy in the 20 percent of ALS patients with mutations in SOD1 vary based on which mutation they have, but most have muscle weakness and motor neuron death, as well as inclusions containing SOD1 protein.

Instead of using the adenine-to-thymine base editor, the researchers developed a cytosine-to-thymine converter using the coding sequence of Streptococcus pyogenes Cas9 and a guide RNA that targets both wild type and mutant human SOD1 to create an early stop codon. This doesn’t affect the mouse SOD1. In human cells, the split base editor seemed to be even more efficient than when the editor was transfected at full length, hitting about 29 percent of the target sites, compared to the full-length editor’s 19 percent.

Next the authors packaged their split base editor into two AAV backbones and injected them or a control AAV into the animals’ lumbar cerebrospinal fluid when they were around two months old. The vectors ended up primarily in astrocytes, as well as in neurons and microglia. While the researchers didn’t see a difference in symptom onset at around three months, the mice that received the base editor maintained their weight and lived about 10 percent longer than controls. The treated mice also had fewer SOD1-positive inclusions and healthier motor neurons.

“Using base editors to disable the mutant SOD1 gene in astrocytes (a cell type that normally supports healthy nervous system function but in SOD1-ALS exerts toxicity onto motor neurons) led to a marked slowing in disease progression,” Gaj writes in an email to The Scientist. “Since many persons with ALS are diagnosed following the onset of symptoms, pre-clinical strategies that can meaningfully slow the disease are especially important and should be further studied.”

“This is a good indication that base editing actually can be used to treat ALS,”
says Baisong Lu, a gene therapy researcher at Wake Forest School of Medicine who did not participate in the work. He cautions that off-target effects—the base editor can edit both DNA and RNA—and how long the AAV delivery method lasts are both in need of more work before this technique would be safe for people.

The dual AAV strategy could also be expensive, says Mimoun Azzouz, a neuroscientist at the University of Sheffield in the United Kingdom. “Thinking about the clinical development and marketing and the commercialization of this product, you need to manufacture two viruses, and you need to assess these two viruses for safety, so the cost can be extremely high.”

Despite the challenges, the strategy shows promise for translation to humans, Perez-Pinera writes in an email to The Scientist. AAVs are already approved by the Food and Drug Administration for gene therapy, he explains. Plus, using a humanized model of the disease—a mouse that contains the human sequence of the target gene—means that the method validated in mouse models can be translated to people without adapting them to target a different sequence. People who develop ALS due to a mutation in SOD1 also have one good copy of the gene, just like the mice, which have a functioning mouse copy.

“We injected animal models shortly before disease onset. While injecting the animals earlier could improve the outcome of the disease as demonstrated in other studies, the reality is that ALS is not typically diagnosed until the patient experiences symptoms. Our study predicts what can be expected from treating a patient recently diagnosed with the disease,” Perez-Pinera writes.

“We still have some distance to travel before the results in our current study can benefit ALS patients,” Gaj acknowledges. The researchers are working on minimizing off target effects and on developing new delivery methods that could improve efficacy. “We still have a number of important questions to answer and technological hurdles to address before we begin thinking about clinical translation.”

 
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Chemogenetics rescues the health of the molecular network (pink) that surrounds neurons (green)
in laboratory models. Scientists used the technique to delay the onset of ALS symptoms.


Researchers delay onset of ALS in laboratory models

by University of Toronto | Medical Xpress | 20 April 2020

A team of researchers led by scientists at the University of Toronto (U of T) has delayed the onset of amyotrophic lateral sclerosis (ALS) in mice. They are cautiously optimistic that the result, combined with other clinical advances, points to a potential treatment for ALS in humans.

Commonly known as Lou Gehrig's disease, ALS is caused by the degeneration and loss of neurons that control muscles. There is no cure for ALS which currently affects between 2,500 and 3,000 Canadians.

"Our experiment profoundly delayed the disease by preventing the degeneration of neurons in the cortex of the brain," says Melanie Woodin, a professor in the Department of Cell & Systems Biology (CSB) at U of T and a co-author of a study published recently in Brain.

"It delayed typical symptoms of ALS like the deterioration of motor skills and weight loss. It also increased the survival rate."

The result was achieved in mice that possessed the same gene mutation (SOD1) found in some human ALS patients. The researchers targeted neurons in the motor cortex—the region of the brain that controls muscles—with an engineered protein designed to correct an imbalance in neurons referred to as hyperexcitability.

"Neurons communicate with each other through synaptic transmission, which involves both the release of chemical neurotransmitters and electrical activity" explains Woodin. "This communication can be either excitatory or inhibitory. Excitation is like the gas pedal in your car and inhibition is the brake pedal. Too much gas and you'll speed off the road; too much brake and you don't go anywhere. So, to drive properly, you need a balance between the two."

In a healthy brain, a balance between excitation and inhibition ensures proper brain function—enabling us to solve math problems, retrieve memories and feel emotion. But too much excitation in the brain's neurons can lead to neurological disorders like seizures, epilepsy, neuropathic pain, autism spectrum disorders, schizophrenia and ALS.

While human SOD1 gene mutation carriers display pronounced cortical hyperexcitability in the decade prior to the onset of ALS, it wasn't clear it was a cause of neuronal degeneration. "We knew before that there was a very profound imbalance between excitation and inhibition in the region of the brain that controls movement," says Woodin. "But that didn't tell us whether this hyperexcitability caused the onset of symptoms."

"Now we know,"
says Woodin. "That in ALS mice with the SOD1 mutation, hyperexcitability in the motor cortex is causal to the onset of the disease."

A path to a potential treatment in humans

"The result is important because it points down a path for a potential treatment in humans," says Woodin, who is also the dean of U of T's Faculty of Arts & Science.

The optimism that the result could eventually lead to a treatment in humans is bolstered by the fact that it comprises advances which have yet to be used together but that are proven on their own.

Woodin and her colleagues are combining advances in viral technology with a revolutionary technique in neuroscience called chemogenetics. Proteins that had their structure altered were introduced into mice via a virus and delivered to neurons in the primary motor cortex.

Once there, they were activated with a pharmaceutical drug—but one which isn't approved for use in humans. However, other scientists demonstrated that a drug called clozapine, which is approved for use in humans for the treatment of certain psychiatric disorders, could also activate the protein.

"The clozapine discovery was a game-changer for our work," says Woodin. "It revealed a clear path for clinical translation which just wasn't there when we first developed our hypothesis."

And while chemogenetics was employed in the current study, it isn't currently used in human patients in part because of the challenge in delivering the chemogenetic "tool" to the right neurons. But an innovation being pioneered for human use by Dr. Lorne Zinman and Dr. Agessandro Abrahao offers a promising alternative.

Zinman and Abrahao are testing a non-invasive procedure to deliver therapeutic agents to the motor cortex of ALS patients. The brain is protected by a natural barrier that keeps out pathogens like bacteria and viruses—but that also keeps out therapeutics like drugs and proteins. With the new technique, the blood brain barrier can be temporarily and safely opened to deliver a protein to targeted regions of the brain.

Zinman, a co-author on the paper, runs the ALS clinic at Sunnybrook Health Sciences Centre and is an associate professor at the University of Toronto. Abrahao is an assistant professor in the Department of Medicine at U of T and an associate scientist at Sunnybrook.

"This advancement in decreasing cortical hyperexcitability has the potential to have a major impact on treating ALS in humans," says Zinman. "Much more work is needed but this advance shows great promise toward a path to stopping this disease."

According to Dr. David Taylor, vice president of research at ALS Canada, "Despite the fact that both upper motor neurons in the cortex and lower motor neurons in the body are degenerating in ALS, much of the research to date has ignored the role of upper motor neurons."

"Excessive activity of the upper motor neurons could be an important contributor to the disease and Professor Woodin's work focused on a novel way to stimulate neighbouring neurons that can put the brakes on this abnormal biology,"
says Taylor. "Her results in ALS model mice are exciting and hopefully this can someday be a treatment strategy tested in human clinical trials."

 
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Richard Myers, PhD, and Nicholas Cochran, PhD, in the Myers Lab.

Scientists uncover a gene that doubles the risk of developing ALS

by HudsonAlpha Institute for Biotechnology | Medical Xpress | 27 April 2020

Scientists at the HudsonAlpha Institute for Biotechnology, the University of California, San Francisco (UCSF), and the University of Alabama at Birmingham (UAB), have identified a new risk factor for multiple neurodegenerative diseases.

"Finding evidence for a risk factor that contributes to multiple neurodegenerative diseases is exciting," said Richard M. Myers, Ph.D., HudsonAlpha president and science director. "We already know that these diseases share some pathologies. This work shows that the underlying causes of those pathologies may also be shared."

In the study, which was published April 23 in the American Journal of Human Genetics, researchers sequenced and analyzed whole genomes of more than 1,100 people. They found that rare variation in the gene TET2 nearly doubled the risk of developing Alzheimer Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Fronto-Temporal Dementia (FTD).

"The project wouldn't have been possible without extensive collaboration between institutions," said first author Nicholas Cochran, Ph.D., a senior scientist in the Myers Lab. "You end up being able to find things that you can't find working alone."

Jennifer Yokoyama, Ph.D., an assistant professor of neurology at UCSF, worked with Cochran on technical details and also was the point person for sample collection. The majority of the samples used for the project were collected over decades at the UCSF Memory and Aging Center and then sequenced and analyzed at HudsonAlpha.

Once the research team had the sequence results, they analyzed the genomes of 493 people with either AD, ALS, or FTD and 671 healthy people. Many of the patients had early-onset versions of neurodegenerative disease, which suggests that it is more likely that there would be a genetic component of their illness. During genome analysis, the researchers looked at both coding and non-coding regions of the genome for DNA sequence variants, a strategy that allowed them to be more confident that any possible genes they pulled out were the real deal.

"We didn't go in with any suspicions about what we might get, so we're excited that we did find a new genetic association," Cochran said. TET2 is especially exciting because it encodes a protein that catalyzes DNA demethylation. Previous work has shown that changes in DNA methylation happen during aging, so the authors hypothesize that mutations in the gene could lead to a faulty TET2 protein that disrupts how the brain ages and contributes to the development of neurodegenerative diseases.

"Sometimes we get a hit, and it's hard to understand what it might be doing, but TET2 already has established roles in the brain. So this finding really made sense," Cochran explained.

After the team identified TET2, they looked at previously generated genetic data from more than 32,000 healthy people and people with neurodegenerative diseases. This data confirmed that variants in TET2, in both protein-coding and non-coding regions, were more likely to be present in the genomes of people with AD, ALS, or FTD than in people without these diseases. Next steps will focus on how changes in TET2 levels or function could contribute to aging and neurodegenerative disease.

 
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ALS and gut bacteria linked in “remarkable” new Harvard study.

Gut microbiome influences ALS outcomes

Harvard | Neuroscience News | 15 May 2020

Study reveals a new gut-brain connection in amyotrophic lateral sclerosis (ALS). The gut microbiome could influence the severity of the neurodegenerative disease. Altering the bacteria in the gut may prevent or improve symptoms of ALS.

Harvard University scientists have identified a new gut-brain connection in the neurodegenerative disease amyotrophic lateral sclerosis, or ALS. The researchers found that in mice with a common ALS genetic mutation, changing the gut microbiome using antibiotics or fecal transplants could prevent or improve disease symptoms.

Published in the journal Nature, the findings provide a potential explanation for why only some individuals carrying the mutation develop ALS. They also point to a possible therapeutic approach based on the microbiome.

“Our study focused on the most commonly mutated gene in patients with ALS. We made the remarkable discovery that the same mouse model — with identical genetics — had substantially different health outcomes at our different lab facilities,” said Kevin Eggan, Harvard professor of stem cell and regenerative biology. “We traced the different outcomes to distinct gut microbial communities in these mice, and now have an intriguing hypothesis for why some individuals carrying this mutation develop ALS while others do not.”

Different facilities, different outcomes

The researchers initially studied the ALS genetic mutation by developing a mouse model at their Harvard lab facility. The mice had an overactive immune response, including inflammation in the nervous system and the rest of the body, which led to a shortened lifespan.

In order to run more detailed experiments, the researchers also developed the mouse model in their lab facility at the Broad Institute, where Eggan is the director of stem cell biology at the Stanley Center for Psychiatric Research. Unexpectedly, although the mice had the same genetic mutation, their health outcomes were dramatically different.

“Many of the inflammatory characteristics that we observed consistently and repeatedly in our Harvard facility mice weren’t present in the Broad facility mice. Even more strikingly, the Broad facility mice survived into old age,” said Aaron Burberry, postdoctoral fellow in the Eggan lab and lead author of the study. “These observations sparked our endeavor to understand what about the two different environments could be contributing to these different outcomes.”

Searching the gut microbiome

Looking for environmental differences between the mice, the researchers honed in on the gut microbiome. By using DNA sequencing to identify gut bacteria, the researchers found specific microbes that were present in the Harvard facility mice but absent in the Broad facility mice, even though the lab conditions were standardized between facilities.

“At this point, we reached out to the broader scientific community, because many different groups have studied the same genetic mouse model and observed different outcomes,” Burberry said. “We collected microbiome samples from different labs and sequenced them. At institutions hundreds of miles apart, very similar gut microbes correlated with the extent of disease in these mice.”


The researchers initially studied the ALS genetic mutation by developing a mouse model.

The researchers then tested ways to change the microbiome and improve outcomes for the Harvard facility mice. By treating the Harvard facility mice with antibiotics or fecal transplants from the Broad facility mice, the researchers successfully decreased inflammation.

Gut-brain connection

By investigating the connection between genetic and environmental factors in ALS, the researchers identified an important gut-brain connection. The gut microbiome could influence the severity of disease — whether individuals with the genetic mutation develop ALS, the releated condition frontotemporal dementia, or no symptoms at all — and could be a potential target for therapy.

“Our study provides new insights into the mechanisms underlying ALS, including how the most common ALS genetic mutation contributes to neural inflammation,” Eggan said. “The gut-brain axis has been implicated in a range of neurological conditions, including Parkinson’s disease and Alzheimer’s disease. Our results add weight to the importance of this connection.”

 
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Ride For Life presents CSHL with $300,000 for ALS research.

ALS-like symptoms linked to retrovirus

by Joana Carvalho PhD | ALS News Today | 9 Jun 2020

Treatment of people whose symptoms are suggestive of ALS but likely linked to a retrovirus called human T-cell lymphotropic virus type I (HTLV-I) should focus on alleviating symptoms and lowering the viral load, a case report highlights.

The report, “Human T-cell Lymphotropic Virus Type I Associated with Amyotrophic Lateral Sclerosis Syndrome: Immunopathological Aspects and Treatment Options,” was published in the journal Cureus.

Human T-cell lymphotropic virus type I (HTLV-I) is a retrovirus that infects immune T-cells. It has been associated with different types of blood cancers, infectious myelopathies (spinal cord infections), and ALS.

Cases are known of patients showing mixed symptoms of multiple disorders associated with HTLV-I, which in some instances can make it difficult to determine appropriate treatment.

Physicians in Colombia described a 49-year-old woman who tested positive for HTLV-I, and showed signs of motor neuron disease — a disorder in which the nerve cells responsible for controlling voluntary movements become damaged — that were suggestive of ALS.

The woman was from Buenaventura, a region in Colombia where HTLV-I is considered endemic, meaning always present in the population at a given frequency. She had no relevant medical history, but noted progressive symptoms of pain and weakness over the previous 9 months. These symptoms started in her legs, and progressively started to affect her arms. She also had difficulties speaking, swallowing, and supporting her head and body. Eventually, she lost all mobility and was bedridden.

Lab tests found no signs of a metabolic disorder or an infectious disease, and no gastrointestinal abnormalities. However, a blood test indicated she was producing antibodies against HTVL-I, suggesting that she could have been infected by the virus. Still, no antibodies were found in her cerebrospinal fluid. MRI scans found brain lesions, and signs of nerve degeneration that did not compromise the spinal cord.

Electrophysiology studies also found abnormalities in the transmission of electrical signals in the nerves of her legs, while electromyography studies found signs of denervation (loss of nerve supply) in the muscles of her legs, arms, and neck, which were all indicative of a motor neuron disease.

Of note, electrophysiology studies assess the generation and transmission of electrical signals in neurons, or nerve cells, while electromyography does the same thing in muscles.

Based on these findings, physicians concluded the woman had a motor neuron disease and was likely “in the asymptomatic carrier phase for the HTLV-I virus.” Nevertheless, they did not rule out the possibility that her symptoms could be a direct result of the virus itself.

“Patients infected by the virus can remain in the state of being asymptomatic carriers for a long time,” the researchers wrote, adding that "assessing the levels of antibodies against HTVL-I in the blood and CSF is important to differentiate between patients with high viral load and ALS-like symptoms directly affected by the virus and patients who are asymptomatic carriers with low viral load.”

The woman was started on riluzole (brand name Rilutek, marketed by Sanofi), an approved oral treatment for ALS, along with methylprednisolone, an anti-inflammatory, for three days. This was followed by prednisone, a corticosteroid, and gabapentin-type pain modulators as her symptoms improved. Rehabilitation and integral care were also given before she was discharged.

“The HTLV-I virus is associated with central and peripheral nervous system involvement, and treatment should focus on symptomatic management and eliminating infected cells to reduce the viral load by using such medications as steroids, valproic acid, the antiviral zidovudine, and mogamulizumab,” the authors concluded.

 
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ALS drug generates promising clinical trial results

by Massachusetts General Hospital | Medical Xpress | 2 Sep 2020

An experimental medication slows the progression of the neurodegenerative disease called Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, according to recently released results from a clinical trial run by investigators at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH) and Amylyx Pharmaceuticals, Inc., the company that manufactures the medication. The findings, reported in the New England Journal of Medicine, offer hope that a treatment may one day be available for patients with ALS, a fatal condition with no cure that attacks the nerve cells in the brain and the spinal cord to progressively hinder individuals' ability to move, speak, eat, and even breathe.

Called AMX0035, the oral medication is a combination of two drugs, sodium phenylbutyrate and taurursodiol, that each target a different cell component important for protecting against nerve cell death.

In the CENTAUR trial, 137 participants with ALS were randomized in a two-toone ratio to receive AMX0035 or placebo. Over six months, participants who were treated with AMX0035 had better functional outcomes than those treated with placebo as measured by the ALS Functional Rating Scale (ALSFRS-R), a questionnaire that evaluates several activities of daily living such as a patient's ability to walk, hold a pen or swallow food.

"The participants treated with AMX0035 demonstrated a significant slowing of ALS disease progression as measured by the ALSFRS-R. This is a milestone in our fight against ALS," said Sabrina Paganoni, MD, Ph.D., principal investigator of the CENTAUR study, investigator at the Healey & AMG Center for ALS at MGH, and assistant professor of PM&R at Harvard Medical School (HMS) and Spaulding Rehabilitation Hospital. Paganoni noted that the trial involved a partnership between industry, foundations such as the ALS Association and ALS Finding a Cure and academia, with input from world-renowned leaders in neurology and drug development.

Senior author Merit Cudkowicz, MD, director of the Healey & AMG Center for ALS at MGH, chief of Neurology at MGH, and the Julieanne Dorn Professor of Neurology at HMS, commented, "Amylyx took a novel approach to the problem of motor nerve cell dysfunction. With guidance from our team and in collaboration with our colleagues in the Northeast ALS Consortium (NEALS), Mass General Biostats and the Barrows Neurological Institute, the clinical trial moved forward quickly and carefully. We are proud of this important study. We are also very thankful to the participants and their families for their key role in advancing research."

In 2015, Amylyx co-founders and co-CEOs Joshua Cohen and Justin Klee were introduced to Cudkowicz through a colleague and shared their vision for AMX0035. The teams decided that MGH's expertise in designing and leading clinical trials and Amylyx's potential treatment would make for a great collaboration. Cudkowicz introduced them to Paganoni and to the science advisory committee for NEALS, a trial network Cudkowicz co-founded. Soon after, the CENTAUR Trial came to fruition and sites throughout the NEALS consortium began enrolling patients.

"Today's news builds upon the progress we have made in ALS research," said Cohen. "This experimental medicine has demonstrated that it can help patients retain their physical function, which is an incredible feat given the debilitating nature of this disease. It is our hope that AMX0035 will one day be available for patients and we are committed to making that a reality."

"Patients and their families do not have time to wait,"
said Klee. "People with ALS progressively lose their ability to function and care for themselves, so we want to do everything we can to help them slow down this devastating disease. We will be working with the FDA to determine next steps and the path for patients to gain access to AMX0035. We'll continue to share our plans with the community as they develop."

An Open Label Extension trial, in which all patients in the study have been offered AMX0035, is ongoing to assess the medication's long-term impact.

Explore further : Experimental drug shows early promise against inherited form of ALS, trial indicates

 
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New drug combo for ALS slows decline in small clinical study

by Jef Akst | The Scientist | 3 Sep 2020

After six months, patients with fast-progressing amyotrophic lateral sclerosis who had received the experimental treatment had less loss of function than those who received a placebo.

trial of 137 patients with amyotrophic lateral sclerosis showed that a new combination of an existing drug and a supplement lessened declines in a standard measure of function over six months, according to a study published today in The New England Journal of Medicine.

"While the effect was modest and the trial early stage, I am convinced that we are at the beginning of a new era in ALS treatment discovery,” Sabrina Paganoni, a researcher at the Sean Healey & AMG Center for ALS at Massachusetts General Hospital and Harvard Medical School who led the study, tells NPR. “Patients want to be able to continue to use their hands so they can cut their own food and type emails, or they want to be able to walk and climb stairs, and this is exactly what we measured in the trial.”

There are currently two approved drugs to treat ALS: riluzole, which can extend lifespan by an average of a few months and has been on the market for 25 years, and the 2017-approved edaravone, which was shown in clinical trials to help patients function for longer into their disease. Even with these treatment options, ALS is still a death sentence for most patients, typically within three to five years of diagnosis.

The new drug combo, called AMX0035, was conceived by Joshua Cohen and Justin Klee as undergraduates at Brown University several years ago and is now being developed by the company they founded, Cambridge, Massachusetts–based Amylyx. The treatment includes sodium phenylbutrate, which is a medication for urea cycle disorders, and the supplement taurursodiol—a combo that Cohen hypothesized back in 2013 as a biomedical engineer major would maintain functioning of the mitochondria and endoplasmic reticulum to protect against neuronal damage, The New York Times reports.

The data from the trial suggested it might be working. In six months, patients who had received AMX0035 saw a smaller decline in the ALS Functional Rating Scale, which assesses a patient’s ability to do activities such as swallow and climb stairs, than those in the placebo group—about 2.9 points less, on average. Most also saw improvement in certain fine motor skills. “Even a small change in a couple of points can mean a large change in what daily life looks like,” Paganoni tells STAT.

“This is very encouraging,” Neil Shneider, the director of the Eleanor and Lou Gehrig A.L.S. Center at Columbia University who did not participate in the study, tells the Times. “The question is, is the effect on function sustained beyond the six-month trial period and does it have an effect on survival?” Matthew Kiernan, chair of neurology at the University of Sydney who was also not involved in the research, points out to STAT that the trial found no evidence that the treatment improved patients’ ability to breathe, but says he awaits future results from Amylyx.

Most of the patients in the trial were already taking an approved drug, and they continued their normal regimen throughout the trial of AMX0035. Merit Cudkowicz, director of the Healey Center and senior author of the study, tells the Times that, if approved, the new treatment would likely be used in combination with existing medications.

The trial was the first supported with funds from the ALS Association that were generated by the Ice Bucket Challenge, the Times reports, and if the drug is approved, Amylyx will repay 150 percent of the ALS Association’s funding to support additional research.

“What makes this time so exciting is there are over 50 different clinical trials that are enrolling and recruiting ALS patients right now,” Kuldip Dave, the ALS Association’s vice president of research, tells NPR. “And they’re all going after different targets.”

 
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ALS is the progressive degeneration of motor neurons
that control people’s muscles.

Investigational drug stops toxic proteins tied to ALS

University of Pennsylvania | Neuroscience News | 8 Sep 2020

c9ASO, an investigational ASO drug, targets the TDP-43 protein, reducing its buildup and decreasing neurological decline associated with ALS and FTD.

An investigational drug that targets an instigator of the TDP-43 protein, a well-known hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), may reduce the protein’s buildup and neurological decline associated with these disorders, suggests a pre-clinical study from researchers at Penn Medicine and Mayo Clinic. Results were published in Science Translational Medicine.

The work shows, for the first time, how toxic poly(GR) (glycine-arginine repeat) proteins produced by the mutated C9orf72 gene stimulate the clumping of TDP-43 found in ALS, also known as Lou Gehrig’s disease, and FTD patients. In a mouse model, the researchers also show that treatment with a pipeline drug known as an antisense oligonucleotide (ASO) reduced the levels of poly(GR), TDP-43 clumps, and neurodegeneration along with it.

“A common genetic cause of ALS and FTD is a repeat expansion in the C9orf72 gene, which somehow leads to TDP-43 aggregation in degenerating neurons, but what remained unclear until now was how those two were connected,” said co-senior author James Shorter, PhD, a professor of Biochemistry and Biophysics in the Perelman School of Medicine at the University of Pennsylvania. “We found that TDP-43 aggregates much more rapidly if these toxic poly(GR) proteins are around, suggesting a direct link between the mutation, poly(GR), and TDP-43.”

"ALS is the progressive degeneration of motor neurons that control people’s muscles, speech, and ability to breathe. FTD, the most common form of dementia in people under 60, results in damage to the anterior temporal and/or frontal lobes of the brain; as it progresses, it becomes increasingly difficult for people to function and even care for oneself."

“This finding presents an exciting potential therapeutic target to treat these debilitating diseases by lowering poly(GR) levels,”
added Hana Odeh, PhD, a post-doctoral fellow in the Shorter lab and co-first author.

After researchers in the Shorter lab demonstrated the role of poly(GR) proteins in TDP-43 accumulation at the protein level, their colleagues at Mayo Clinic in Jacksonville, Fla., studied the interactions in both human cells and mice to support the initial bench side finding at Penn. Co-senior authors from Mayo Clinic include Yongjie Zhang, PhD, an assistant professor of Neuroscience, and Leonard Petrucelli, PhD, Ralph and Ruth Abrams Professor of Neuroscience at Mayo Clinic College of Medicine and Science.

They showed in a series of complementary experiments, including immunofluorescence staining and immuno-electron microscopy, that poly(GR) in human cells alone can sequester TDP-43 proteins, and in doing so induce the formation of dense protein clumps. This same mechanism was then demonstrated in a mouse model.

"It’s worth noting," the researchers said, "that the burden of both TDP-43 and poly(GR) correlate with neurodegeneration in patients observed in past studies: the higher the protein levels, the worse the neurological function, providing further evidence that the two proteins are conspiring."

Next, the team delivered an ASO drug known as c9ASO, which is being investigated in clinical trials, into the brains of three-month old mice expressing the ALS/FTD-causing repeat-expansion and found that it had diminished the levels of both poly(GR) and TDP-43 aggregates. c9ASO has been shown to switch off the repeat expansions in the C9orf72 gene and reduce poly(GR), but this is the first time it’s been shown to reduce TDP-43 clumping.

To assess the drug’s neuroprotective ability, the researchers examined the amount of neurons and plasma neurofilament light (NFL), a known biomarker of neurodegeneration in patients, in treated mice. The drug prevented the reduction of cortical neurons and decreased levels of plasma NFL, they found, suggesting the drug helped confer neuroprotection. “If that extends to patients, the plasma NFL level provides a way to track how effective your therapeutic is,” Odeh said.

The researchers plan to study in more detail how TDP-43 and poly(GR) and other similar toxic proteins associated with the mutated C9orf72 interact, and conduct further studies with ASO drugs to better understand their role in stopping the clumping of TDP-43.

“This exciting collaborative study sets the stage for continued teamwork in this space, which I see as being of great interest to the ALS and FTD community,” Shorter said.

 
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ALS researchers take ‘significant step’ toward new treatment

by Chris Melore | Universities of Liverpool and Nagoya | 2 Oct 2020

The world’s awareness about Amyotrophic lateral sclerosis (ALS) has remained high for decades. Despite constant research however, there are few options which help treat the condition and none that cure it. Now, an international team says a new drug may finally help delay the death of nerve connections in ALS patients.

Scientists from the Universities of Liverpool and Nagoya find a Selenium-based drug-molecule called Ebselen and other compounds can change the toxic properties of a protein linked to ALS. A mutation in this protein, superoxide dismutase (SOD1), can cause ALS — especially cases believed to be passed through family genes.

Why is ALS so deadly?

ALS, also known as Lou Gehrig’s disease and motor neuron disease, is a degenerative disease which attacks the brain and muscles. This incurable condition slowly breaks down the nerve links between the brain and body, eventually causing paralysis. Most patients also lose the ability to speak without assistance and die within two and five years of their diagnosis.

About 20 percent of the familial ALS cases show a connection to dominant mutations in the SOD1 gene. Until now, only two drugs show limited results in treating these mutant proteins. Riluzole was approved for use in 1995 and edaravone in 2017.

“Choices are very limited for a current ALS therapy, therefore, we are excited to take a significant step forward for developing a new class of drug candidate for ALS,” Professor Koji Yamanaka of Nagoya University says in a media release.

How does Ebselen work?

The new drug compound focuses on stabilizing the SOD1 structure. The team says in vitro therapeutic trials reveal Ebselen is significantly more potent than edaravone. Experiments on mice show the drug clearly delays the onset of ALS, including the creation of ligand-bound A4V SOD1. This mutant protein is known to cause the most severe disease outcomes.

“The fact that this new generation of organo-selenium compounds have better in vitro neuroprotective activity than edaravone holds a significance promise for the potential of this class of compounds as an alternative therapeutic agent for ALS treatment,” study leader Samar Hasnain explains.

Hasnain adds these compounds could possibly have other benefits, including defending against viral diseases like COVID-19.

The study appears in the journal EBioMedicine.

 
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The two-drug combination was conceived seven years ago by Justin Klee, left, and Joshua Cohen.

Drug may extend ALS patients’ lives by several months

by Pam Belluck | New York Times | 16 Oct 2020

The two-drug combination invented by college students is one of many potential therapies being tested for this paralyzing fatal condition.

A potential therapy for amyotrophic lateral sclerosis, a fatal neurological disorder, may allow patients to live several months longer than they otherwise would have, according to a study published Friday.

The two-drug combination, dreamed up by two college students, is one of several potential treatments raising the hopes of patients with ALS., also known as Lou Gehrig’s disease. The paralytic condition steals people’s ability to walk, speak, eat and ultimately breathe, typically causing death within two to five years.

There are only two approved ALS. medications, neither very effective. But advocacy efforts by patients and organizations, along with the Ice Bucket Challenge, a highly successful fundraising campaign, have galvanized research into more than 20 therapies that are currently in clinical trials.

The two-drug combination, called AMX0035, was conceived seven years ago by Joshua Cohen and Justin Klee, then a junior and senior at Brown University, with the goal of preventing the destruction of neurons that occurs in many brain disorders. It is a combination of an existing supplement and a medication for a pediatric urea disorder.

Last month, a study of 137 patients reported that AMX0035 slowed progression of ALS paralysis by about 25 percent more than a placebo. Measuring patients using a scale of physical function, researchers found that those receiving a placebo declined in 18 weeks to a level that patients receiving the treatment didn’t reach until 24 weeks, according to the study’s principal investigator, Dr. Sabrina Paganoni.

But because that trial was conducted for only 24 weeks, it left unanswered a crucial question of whether the treatment extended survival for the patients receiving the therapy. After that study ended, 98 of the participants, who had not been told whether they had received placebo or therapy, were given the option of taking the therapy for up to 30 months, a format called an open-label extension study.

Ninety patients did so, including 34 from the placebo group, who began taking AMX0035 about seven months after the 56 who had received it from the beginning. The research team, led by Dr. Paganoni, a neuromuscular medicine specialist at Massachusetts General Hospital’s Healey & AMG Center for ALS, and Dr. Merit Cudkowicz, the Healey Center’s director, followed the patients over nearly three years.

The new study, published in the journal Muscle and Nerve, reported that people who received AMX0035 during the trial and through the open-label extension lived about 6.5 months longer than people who had originally received the placebo — a median of 25 months compared to 18.5 months.

“In addition to the significant functional benefit previously reported, people taking AMX0035 appear to live several months longer,” said Neil Thakur, chief mission officer of the ALS Association, which gave a grant for a portion of the study, most of which was financed by the drug maker. “That is a very meaningful benefit for people affected by this devastating, fatal disease.”

The ALS Association is urging the Food and Drug Administration to expedite its review process and grant approval as soon as the company applies for it — but to require rigorous follow-up studies, since the original study was a Phase 2 trial instead of the larger and longer Phase 3, which is often required for approval. The association also wants the company that makes the treatment, Amylyx, a Massachusetts start-up the students founded, to seek the agency’s permission to provide the drug for compassionate use while it is still being evaluated.

Experts who weren’t involved in the study said the data was encouraging, but that important unanswered questions remained about the potential therapy. One unknown is what benefit the drug would have when compared with patients who never received it at all and received only placebo for 30 months, said Dr. Robert Miller, director of clinical research at Forbes Norris MDA/ALS Research Center at California Pacific Medical Center. Still, he said he considered the results a “base hit single.”

The study involved patients who developed symptoms within 18 months before the trial and were affected in at least three body regions, generally signs of fast-progressing disease. Most were already taking one or both of the approved A.L.S. medications: riluzole, which can extend survival by several months, and edaravone, which can slow progression by about 33 percent. That could suggest that AMX0035 — a powder that patients mix with water to drink or ingest through a feeding tube twice daily — might work on top of existing treatments.

Researchers said that according to a statistical model that included factors like patients’ age and their score on a 48-point ALS functional scale before they entered the trial, patients who received AMX0035 from the beginning had a 44 percent lower risk of death during the study period.

Dr. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, who wasn’t involved in the trial, said that the data suggested a “powerful impact that’s pretty striking” in extending survival for patients who got the drug for the 24 weeks of the trial — when they were earlier in the disease than patients who started the drug after the trial.

But, he said, it wasn’t clear how much those who first received 24 weeks of placebo benefited when they took the drug. “It could mean that the drug is really effective and people who got the drug late really would have been dead at 12 months instead of 18,” Dr. Koroshetz said. “Or, the other way of thinking about it is that the drug is not effective unless you get it early. There’s no clue here to which one of those is true.”

Dr. Koroshetz also said that the reality that many of the patients ultimately died “emphasizes how devastating A.L.S. is.”

“Even for the people who got the drug early and continued to get the drug,” he noted, “there’s still only 2.5 years’ survival.”

 
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Investigational ALS drug prolongs patient survival in clinical trial

by Massachusetts General Hospital | Medical Xpress | 16 Oct 2020

An experimental medication that was recently shown to slow the progression of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, has now demonstrated the potential to also prolong patient survival. The findings come from a clinical trial conducted by investigators at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH) and Amylyx Pharmaceuticals, Inc., the company that manufactures the medication. Amylyx developed AMX0035, the investigational neuroprotective therapy evaluated in the CENTAUR trial and designed to reduce the death and dysfunction of motor neurons.

ALS, a degenerative condition without a cure, attacks brain and spinal cord nerve cells to progressively affect individuals' ability to move, speak, eat and even breathe. The new results, reported in the journal Muscle and Nerve, provide additional proof of the benefits that patients with ALS may experience when taking the oral drug called AMX0035, which is a combination of sodium phenylbutyrate and taurursodiol. These components target oxidative stress within nerve cells' energy-producing mitochondria and protein-processing endoplasmic reticulum to help prevent neurodegeneration.

In the CENTAUR trial, 137 participants with ALS were randomized two-to-one to receive AMX0035 or placebo. Recently, investigators demonstrated that AMX0035 slowed ALS disease progression over six months, with impacts on various activities of daily living such as a patient's ability to walk, talk, use utensils or swallow food. Patients who completed CENTAUR were eligible to participate in an open-label extension (in which all patients received AMX0035) aimed at assessing the long-term safety and efficacy of the medication.

Investigators' nearly three-year survival analysis incorporated all participants who enrolled in CENTAUR, whether they continued long-term treatment with AMX0035 in the open-label extension or not. The team found that participants originally randomized to receive AMX0035 lived for a median of 6.5 months longer than those originally randomized to receive the placebo.

"These findings are an important step forward because, in this trial, early treatment with AMX0035 was associated with longer survival in people with ALS," said the study's leader Sabrina Paganoni, MD, Ph.D., investigator at the Healey & AMG Center for ALS and assistant professor of Physical Medicine and Rehabilitation at Harvard Medical School and Spaulding Rehabilitation Hospital. "These results provide substantial evidence supporting the role of AMX0035 for the treatment of ALS. Next steps will depend on ongoing discussions with regulatory agencies."

Senior author Merit Cudkowicz, MD, director of the Healey & AMG Center for ALS at MGH, chief of Neurology at MGH, and the Julieanne Dorn Professor of Neurology at Harvard Medical School, added: "This is one of the first studies to show effect on both function and survival. We are hopeful that this is just the beginning of many new treatments for ALS."

 
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A team of MIT researchers has now designed a stretchable, skin-like device that can be
attached to a patient's face and measure small movements such as a twitch or a smile.


A wearable sensor to help ALS patients communicate

by Massachusetts Institute of Technology | Medical Xpress | 22 Oct 2020

People with amyotrophic lateral sclerosis (ALS) suffer from a gradual decline in their ability to control their muscles. As a result, they often lose the ability to speak, making it difficult to communicate with others.

A team of MIT researchers has now designed a stretchable, skin-like device that can be attached to a patient's face and can measure small movements such as a twitch or a smile. Using this approach, patients could communicate a variety of sentiments, such as "I love you" or "I'm hungry," with small movements that are measured and interpreted by the device.

The researchers hope that their new device would allow patients to communicate in a more natural way, without having to deal with bulky equipment. The wearable sensor is thin and can be camouflaged with makeup to match any skin tone, making it unobtrusive.

"Not only are our devices malleable, soft, disposable, and light, they're also visually invisible," says Canan Dagdeviren, the LG Electronics Career Development Assistant Professor of Media Arts and Sciences at MIT and the leader of the research team. "You can camouflage it and nobody would think that you have something on your skin."

The researchers tested the initial version of their device in two ALS patients (one female and one male, for gender balance) and showed that it could accurately distinguish three different facial expressions—smile, open mouth, and pursed lips.

MIT graduate student Farita Tasnim and former research scientist Tao Sun are the lead authors of the study, which appears today in Nature Biomedical Engineering. Other MIT authors are undergraduate Rachel McIntosh, postdoc Dana Solav, and research scientist Lin Zhang. Yuandong Gu of the A*STAR Institute of Microelectronics in Singapore and Nikta Amiri, Mostafa Tavakkoli Anbarani, and M. Amin Karami of the University of Buffalo are also authors.

A skin-like sensor

Dagdeviren's lab, the Conformable Decoders group, specializes in developing conformable (flexible and stretchable) electronic devices that can adhere to the body for a variety of medical applications. She became interested in working on ways to help patients with neuromuscular disorders communicate after meeting Stephen Hawking in 2016, when the world-renowned physicist visited Harvard University and Dagdeviren was a junior fellow in Harvard's Society of Fellows.

Hawking, who passed away in 2018, suffered from a slow-progressing form of ALS. He was able to communicate using an infrared sensor that could detect twitches of his cheek, which moved a cursor across rows and columns of letters. While effective, this process could be time-consuming and required bulky equipment.

Other ALS patients use similar devices that measure the electrical activity of the nerves that control the facial muscles. However, this approach also requires cumbersome equipment, and it is not always accurate.

"These devices are very hard, planar, and boxy, and reliability is a big issue. You may not get consistent results, even from the same patients within the same day," Dagdeviren says.

Most ALS patients also eventually lose the ability to control their limbs, so typing is not a viable strategy to help them communicate. The MIT team set out to design a wearable interface that patients could use to communicate in a more natural way, without the bulky equipment required by current technologies.

The device they created consists of four piezoelectric sensors embedded in a thin silicone film. The sensors, which are made of aluminum nitride, can detect mechanical deformation of the skin and convert it into an electric voltage that can be easily measured. All of these components are easy to mass-produce, so the researchers estimate that each device would cost around $10.

The researchers used a process called digital imaging correlation on healthy volunteers to help them select the most useful locations to place the sensor. They painted a random black-and-white speckle pattern on the face and then took many images of the area with multiple cameras as the subjects performed facial motions such as smiling, twitching the cheek, or mouthing the shape of certain letters. The images were processed by software that analyzes how the small dots move in relation to each other, to determine the amount of strain experienced in a single area.

"We had subjects doing different motions, and we created strain maps of each part of the face," McIntosh says. "Then we looked at our strain maps and determined where on the face we were seeing a correct strain level for our device, and determined that that was an appropriate place to put the device for our trials."

The researchers also used the measurements of skin deformations to train a machine-learning algorithm to distinguish between a smile, open mouth, and pursed lips. Using this algorithm, they tested the devices with two ALS patients, and were able to achieve about 75 percent accuracy in distinguishing between these different movements. The accuracy rate in healthy subjects was 87 percent.

Enhanced communication

Based on these detectable facial movements, a library of phrases or words could be created to correspond to different combinations of movements, the researchers say.

"We can create customizable messages based on the movements that you can do," Dagdeviren says. "You can technically create thousands of messages that right now no other technology is available to do. It all depends on your library configuration, which can be designed for a particular patient or group of patients."

The information from the sensor is sent to a handheld processing unit, which analyzes it using the algorithm that the researchers trained to distinguish between facial movements. In the current prototype, this unit is wired to the sensor, but the connection could also be made wireless for easier use, the researchers say.

The researchers have filed for a patent on this technology and they now plan to test it with additional patients. In addition to helping patients communicate, the device could also be used to track the progression of a patient's disease, or to measure whether treatments they are receiving are having any effect, the researchers say.

"There are a lot of clinical trials that are testing whether or not a particular treatment is effective for reversing ALS," Tasnim says. "Instead of just relying on the patients to report that they feel better or they feel stronger, this device could give a quantitative measure to track the effectiveness."

 
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Small brain device a big game changer for severely paralyzed patients

University of Melbourne | Neuroscience News | 28 Oct 2020

A tiny device the size of a small paperclip has been shown to help patients with upper limb paralysis to text, email and even shop online in the first human trial.

The device, Stentrode, has been implanted successfully in two patients, who both suffer from severe paralysis due to motor neuron disease (MND) – also known amyotrophic lateral sclerosis (ALS) – and neither had the ability to move their upper limbs.

Published in the Journal of NeuroInterventional Surgery, the results found the Stentrode was able to wirelessly restore the transmission of brain impulses out of the body. This enabled the patients to successfully complete daily tasks such as online banking, shopping and texting, which previously had not been available to them.

The Royal Melbourne Hospital’s Professor Peter Mitchell, Neurointervention Service Director and principal investigator on the trial, said the findings were promising and demonstrate the device can be safely implanted and used within the patients.

“This is the first time an operation of this kind has been done, so we couldn’t guarantee there wouldn’t be problems, but in both cases the surgery has gone better than we had hoped,” Professor Mitchell said.


Professor Mitchell implanted the device on the study participants through their blood vessels, next to the brain’s motor cortex, in a procedure involving a small ‘keyhole’ incision in the neck.

“The procedure isn’t easy, in each surgery there were differences depending on the patient’s anatomy, however in both cases the patients were able to leave the hospital only a few days later, which also demonstrates the quick recovery from the surgery,” Professor Mitchell said.

Neurointerventionalist and CEO of Synchron – the research commercial partner – Associate Professor Thomas Oxley, said this was a breakthrough moment for the field of brain-computer interfaces.


The device pictured, Stentrode™, has been implanted successfully in two patients, who both suffer from severe paralysis
due to motor neuron disease enabling them to complete such tasks as online banking, shopping and texting.

“We are excited to report that we have delivered a fully implantable, take home, wireless technology that does not require open brain surgery, which functions to restore freedoms for people with severe disability,”
Associate Professor Oxley, who is also co-head of the Vascular Bionics Laboratory at the University of Melbourne, said.

The two patients used the Stentrodeto control the computer-based operating system, in combination with an eye-tracker for cursor navigation. This meant they did not need a mouse or keyboard.

They also undertook machine learning-assisted training to control multiple mouse click actions, including zoom and left click. The first two patients achieved an average click accuracy of 92 per cent and 93 per cent, respectively, and typing speeds of 14 and 20 characters per minute with predictive text disabled.

University of Melbourne Associate Professor Nicholas Opie, co-head of the Vascular Bionics Laboratory at the University and founding chief technology officer of Synchron said the developments were exciting and the patients involved had a level of freedom restored in their lives.

“Observing the participants use the system to communicate and control a computer with their minds, independently and at home, is truly amazing,” Associate Professor Opie said.

“We are thankful to work with such fantastic participants, and my colleagues and I are honoured to make a difference in their lives. I hope others are inspired by their success."

“Over the last eight years we have drawn on some of the world’s leading medical and engineering minds to create an implant that enables people with paralysis to control external equipment with the power of thought. We are pleased to report that we have achieved this.”


The researchers caution that while it is some years away before the technology, capable of returning independence to complete everyday tasks is publicly available, the global, multidisciplinary team is working tirelessly to make this a reality.

The trial recently received a $AU1.48 million grant from the Australian commonwealth government to expand the trial to hospitals in New South Wales and Queensland, with hopes to enroll more patients.

*From the article here:
 
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Breakthrough treatment could be game-changer for 'silent killer’

By Jessica Noll Cincinnati | SPECTRUM | 12 Oct 2020

Greg Canter tries buttoning up his white dress shirt, before finishing off with a black tie and white tuxedo jacket with black trim. But he cannot feel his right hand, cannot get his fingers to work, and has to ask his soon-to-be stepson for help.

The then-39-year-old shook off the numbness as carpel tunnel, since it runs in his family, and went on to celebrate the happiest day of his life.

It was Feb. 17, 2018 — his wedding day.

There are dates throughout his life that are seared into his memory. But what he did not realize is, that date and in that moment, his life was changing forever, or at least life as he knew it.

It was not carpel tunnel. It was amyotrophic lateral sclerosis (ALS) and doctors told him that he had 30 months to live.

"I thought there's no absolute way it could be me. I'm healthy. I've never been to a hospital in my life. I've never been admitted into a hospital. I never had a broken bone. I've never really been sick. I've been active in sports... I mean, my whole life, just been healthy,” Canter said. “And that was the last thing that I would've ever expected."

But his life would pivot once again, when in January 2019, he walked through the doors of a University of Kentucky medical clinic in Lexington, Kentucky. Maybe, he thought, this was no longer a death sentence for him.

That is because a new “breakthrough” treatment for ALS is showing signs of hope — and experts say, it could benefit other neurological diseases as well.

You might know it as Lou Gehrig's Disease or remember it from its social media hype during the Ice Bucket Challenge in 2014, but for Canter and thousands of others, it’s a matter of life or death.

Between 20,000 to 30,000 people are living with ALS — a highly debilitative and progressive nervous system disease — at any given time in the U.S., and there are 5,000 new cases every year, said Dr. Sabrina Paganoni, an investigator and researcher at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital in Boston.

"People with ALS have progressive muscle weakness, which means they progressively lose the ability to do many activities daily like walking, talking, swallow food,” said Paganoni, who is an assistant professor at Harvard Medical School and Spaulding Rehabilitation Hospital and has dedicated her career to studying the motor neuron disease, which affects nerve cells within the brain and spinal cord.

"The disease is rapidly progressing and fatal,” she continued. "It will involve other body regions, so the weakness will get more severe. ALS, oftentimes, strikes people in the prime of their life, so you have perfectly healthy individuals who might be in their 40s or 50s or 60s, who are actively working and living their life when the disease starts."

ALS is ultimately fatal because it affects the diaphragm’s muscles, leaving patients unable to breathe on their own, Paganoni said.

"The (patient) will essentially lose control of the muscles in their entire body, including loss of control of the diaphragm, which is a muscle in our chest area that controls respiration. So, in order to breathe in and out, we have to use muscles,” she explained. "The diaphragm moves up and down with the muscle and that will allow the lungs to expand and breathe in oxygen and then release CO2. We don't think of respiration as a process that is driven by muscles, but it is."

Research has not quite pin-pointed the cause of the disease, however, in very few cases, it has been proven to be genetic, said Dr. Adam Quick, a neurologist at The Ohio State University Wexner Medical Center (OSU).

"It's an interesting disease in that most of the time, it's what we call 'sporadic,' which means it's something that people get and we don't know why — which is true of many diseases in medicine. We don't know what is the thing that triggers it or starts it to begin with, and I think that's true with most cases of ALS,” Quick acknowledged.

Only about 10 percent can be attributed to an abnormal gene, a family history of the disease, as the cause, said Quick, who has been researching ALS for 17 years, including 13 years at OSU, where he treats ALS patients. The remaining 90 percent of those diagnosed with ALS are considered "sporadic" or without a known cause.

Canter is part of that 90 percent.

In 2018, he started noticing a change in his body. The 38-year-old’s right side was weakening.

Although looking back, he said, he started having weakness back in 2015 while he was a school custodian. The sports junkie and avid basketball player — all the way back to his high school glory days for the Bethel-Tate High School Tigers — could not make a three-point shot as he always had before. He just chalked it up to getting older and losing his touch for the game.



Now, he said, he believes it was actually an early symptom.

However, by January 2018, his symptoms were undeniable.

While working in construction, he said, he noticed his right index finger and thumb "just quit working." Over the next year, his right hand continued to lose dexterity and was progressively getting weaker, including in February on his wedding day when he had trouble buttoning his shirt.

Following his 39th birthday, Canter was required to get a physical for his CDL license. So, on Sept. 18, 2018, he went to the doctor for what he thought was a routine check-up and physical so that he could continue his job. But test results showed that he had blood in his urine and muscle atrophy in his right hand. He was promptly referred back to his general physician for further review and testing.

He will never forget the day his doctor uttered three letters into his ear.

It was Oct. 15, 2018.

"I walked in — three minutes. She didn't touch me. I didn't remove any clothing. She looked at my hands. Heard what the doctor told her where I came from,, and she goes, 'ALS,’” Canter recalled.

"I'm like, 'No.'It just threw me for a loop because the only thing I ever knew about ALS was the Ice Bucket Challenge back in '14. I participated in it; my family participated in it. Nobody knew what it was. It was kind of like fun game.”

Later, in 2016, donations from The ALS Association’s Ice Bucket Challenge would finance part of the research for a breakthrough treatment with a $2.2 million grant, Paganoni said.

But for Canter, the game that raised money for throwing a bucket of ice over your head, turned into his new reality on Oct. 17, 2018.

"That's how ALS hits you. Until it hits close to home, nobody really knows nothing about it. That's why it's so in-the-dark deadly,” Canter said. “There's not enough knowledge out there for people."

Two days after his doctor said those three letters to him, he saw a neurologist. After several hours and numerous blood, nerve and muscle tests, the specialist concluded the same fate for Canter.

"He called us into a little room, and he goes, 'It's ALS.' I mean, here I am hoping he'd tell me I had brain cancer. I was hoping he'd tell me I had leukemia, because all of them options, you can fight them. ALS, it's a 100 percent fatal disease; they consider it terminal. The average lifespan is 30 months with ALS. And just not knowing nothing about it, that's really the last thing I wanted to hear,” Canter said.

"When he said that, I thought, 'There's gotta be a way he's wrong,’” he said.

So, he went to another neurologist for a second opinion at The Cleveland Clinic in November 2018.

After four hours of tests, that specialist came to the same medical conclusion: ALS.

Following a third and final diagnosis from UC Health, Canter started rigorous treatment, including working with seven medical professionals to help him through the process, including occupational and physical therapists and a social worker. He was prescribed 23 daily medications, however, most of those drugs did not attack ALS, he said. They only eased some of the discomfort associated with the disease. But one of those treatments did include one of the only two FDA-approved medications specifically for ALS, riluzole — which his doctors told him would expand his life expectancy by a few months.

"At the time, you're given a diagnosis, and I was told one to three years to live, if it extends me one day, then (it) worked.'"

Those first few days, weeks and months were a blur for the now-41-year-old, starting with three opinions all concluding with the same unconscionable diagnosis — and for him, he thought, was a death sentence.

But over time, Canter said, a few extra months was not enough.

"All of these people dying today, should be alive tomorrow in today's world. ALS should not be a terminal illness in 2020,” he said with conviction and determination.

He wanted to do whatever it took to treat his ALS, to prolong his life, even if that meant being what he called, a "guinea pig."

And while Canter was experiencing what he believes now to be early-onset symptoms, two college students were brewing up an idea inside their Brown University dorm room that would, again, change everything for Canter.



Changing lives inside a dorm room

More than seven years ago, 21-year-old Josh Cohen and 22-year-old Justin Klee popped the cork on a bottle of champagne to celebrate the beginning of the rest of their lives — that is to say, potentially saving lives.

While cure is a four-letter word they are not yet ready to use, the young pair believes their drug will advance steps in finding the right treatment combinations allowing those diagnosed with ALS to live longer, more functional lives.

In 2013, Cohen was studying bio-medical engineering and Klee was studying neuroscience at Brown University when they developed an idea out of what they called “scientific intrigue.”

Cohen remembered that early on in their planning stages, he was curious about the science behind neurodegenerative diseases and how best to treat them — going after the cells that are prone to stop working.

“What I ended up coming up with and linking up with Justin on, was an approach to make neurons more resilient — targeting a couple of key cellular death pathways in neurons and then the hope was that if you could keep these neurons alive longer, that it might treat some of these terrible diseases and allow patients to stay functional longer,” Cohen said.

"When we were just starting, I think we were excited about the science but we really had no idea what it meant; what it was going to require to start and build a company,” Cohen said. “I remember when Justin and I started it together, we cracked a bottle of cheap champagne and said, 'Yeah, we're starting a company. Here we go!'"

For Klee, who was personally touched by the effects of neurodegenerative diseases, it was a venture well worth the hard work that was about to mount for them.

"I certainly had in both sides of family — not ALS specifically, but one of my grandfathers had mixed dementia, as it seems most dementias are, we're finding out. But actually, when we started the company, I had another grandfather who passed away from Parkinson’s,” Klee said. “We felt like these are really huge problems and everyone has had some family member, some person they know affected by these diseases, and we thought this was an approach people hadn’t taken."

What really put things into perspective for them regarding ALS and how to treat it, was when they started working with doctors, like Quick and Paganoni, and putting faces to the disease while meeting with their patients — seeing what they deal with, with this disease on a daily basis.

"We just felt like, 'My God, if there's anything we can do to help, we have to do it,” Klee recalled.

And from that, CENTUR AMX0035 was born.

The longtime friends realized they worked well together and we able to tackle issues from each of their backgrounds in a unique way.

"We found from the beginning, in approaching problems, we found that we came at things in different ways,” Klee said. “Josh, with an engineering background, would think a lot about inputs and outputs and processes. Whereas, coming for a neuroscience background, I think I thought about things from a more biology-type approach. I think we found that that was really complimentary in developing the drug."

"When we were initially starting out, I think even just getting things kicked off was the initial goal. I don't think we ever foresaw that this would really get to clinic, get to patients. From the early days, we hoped that we could move it very quickly, but it has been a long journey,"
Cohen said. "A long journey to clinic and a long journey to the data. I certainly don't think we anticipated this would happen and I think we've kind of taken it step-by-step and we're kind of shocked and feel very luck that things are where they are."

The drug, AMX0035, that comes in a powder-filled pouch that can then be dissolved in water for patients to take it orally, he said, is designed to target a couple of key cellular pathways that are involved in the cell's decision to die.

"If you think of neurodegenerative disease broadly, these are diseases where we have a large amount of abnormal cell death,” Cohen continued. “So, our idea with the drug was if we target some of those areas where the cell is making the decision to die, we might be able to slow, or in the best case, stop nerve degeneration and allow patients to retain function longer."

But to prove that AMX0035 was more than just a concept, Klee and Cohen, with the help of several doctors, clinics and medical experts, put together a clinical trial study to understand the drug’s effects and record its data.

"I think for a long time, and still to this day, we realized that going after Alzheimer's, ALS, diseases that, unfortunately have a lot of clinical failure, that there would be a lot of skepticism, and that, honestly, we couldn't be sure that this was a real therapy until we did the right tests — combined with our age and we weren't seasoned bio-tech executives — so, it was really important for us to put as much of the money and our time towards research as possible,” Klee said. "We really wanted the science to drive things and see where it led."



Canter, of Georgetown, Ohio, was on the hunt for anything to help his disease and its rapid progression creating a new physical obstacle for him every day.

"It's a daily struggle when you can't do what you used to do, and a lot times, what you could do yesterday. With ALS, that's how everything is described: 'Today is going to be better than tomorrow.' Tomorrow is always worse than today. It's a downhill roller coaster. You don't get better from ALS. It's not like other diseases, where you have good days and bad days. Every day is worse — every tomorrow is worse than today,” he said, sitting in his chair by the front door and wide picture window, resting his hands on the arms of his tan recliner.

He wears a medical alert bracelet on his wrist, layered with a red rubber bracelet with bold white letters: #ALS Strong, leading to his fingers and hands which now curl under.

"I wouldn't give ALS to my absolute worst enemy in life because I know how bad it is, and I wouldn't give that to anybody,” Canter said.

These days, he cannot walk on his own, he said, using an electronic wheelchair or walker to get from room to room. He struggles with everyday tasks like standing and picking up items like a 2-liter of pop.

"I have the strength of a 2-year-old kid,” he explained. "The easiest way to explain it is, a full-body paralysis from head to toe. The only muscle it doesn't affect is your eyes.”

"Your nerves die in your body and when your nerves die, the muscles that react to your nerves, when the muscles aren't getting used, they eventually dissipate; they eventually waste to where you're skin and bones,”
Canter explained. “I’ve got no pain. No pain at all on my body. I don't hurt. It's just that my legs get so heavy; it's just the weakness and the muscle dying. That's the problem with it. It's a silent killer."

But the effects on his life, he said, are more than physical. He feels like a burden to those who love him.

"You require help, that in the years prior, you never needed — where people have to change their lifestyle, to make your lifestyle. So, it doesn't just affect you, it affects the ones around you,” Canter said.

His mom and dad, who live about 20 minutes away, drive to his house twice a day, once at 12:30 p.m., for lunch and medicine, and then again to make him dinner and more medicine around 6:30 p.m.

He has had to put away his pride, he said, and accept their help. But that was not an easy task.

"You need to ask for help. You don't need to suffer," he said he was told by others he met with ALS. "It means everything. You learn who's there for you, who's got your back and who doesn't."

But more than a burden, he said, "It's an emotional toll that it puts on everybody. They see me dying because of going downhill."

"You never appreciate your body, your hands and legs. You take all that for granted when you have it. Your legs and your arms and your hands are valuable pieces. You never want to lose them. I mean, that's a key component of life — and that's what ALS does, we lose them, lose the ability."

And Canter was ready to fight his disease that was taking away his ability to live life like he used to.

In 2019, he applied to join the AMX0035 clinical trial based in Boston.

But to enter a clinical trial, he had to prove his breathing capacity was at a vital level that was acceptable for the taking the medication. After blowing into an apparatus, he kept falling short by one point for breathing and could not get into the study.

He finally blew a 60 percent and was accepted into the clinical trial in January 2019 through one of the participating clinics at the University of Kentucky.

While it was a blind study, he believes that he received the placebo during the trial because his breathing deteriorated while taking his treatment.

But that would change following the initial trial study.



Trial results, pending FDA approval

The 24-week clinical trial was studied in clinics across the country, like the one Quick runs at OSU and included 137 participants, like Canter. What they found is considered a medical “breakthrough” in ALS treatment, both Quick and Paganoni agree.

"People who received the drug in the trial did better than those who received the placebo,” Paganoni concluded.

In fact, she said, participants on the drug regained physical functions like walking and talking for longer than those without the drug. And ultimately, the outcome of the trial data indicated that it slowed down the progression of the disease.

"We were not able to completely stop and we were not able to reverse the disease, but it is certainly a fantastic step in the right direction. We still have a lot of work to do to really find a cure — something to completely stop or reverse the disease,” said Paganoni, who investigated the drug in an academic setting and helped design the trial and obtained funding through the ALS Association and ALS Finding a Cure, from part of the money raised during the Ice Bucket Challenge in 2014.

Paganoni has been studying and researching ALS for a decade and has been part of the research team on this trial for the past five years, alongside several medical colleagues.

"This is really a hopeful time in ALS research. We're testing more drugs at a faster pace and we're making more progress than ever. I'm really convinced that we're just at the beginning of a new era in the discovery of new treatment for ALS,” she said. "This is definitely a great step forward; something that means that we are making progress, that we're making a dent — that this in a way, hopefully, just the beginning of many more new treatments for ALS."

AMX0035 is not currently available for prescription to patients outside of the trial because it is still being investigated at this time and awaiting FDA approval. However, what Paganoni saw in a relatively short amount of time over six months, she said, was that the drug slowed down the progression of the disease, and those findings were published by Paganoni and several other researchers in The New England Journal of Medicine in September.

"As a researcher, I find the data compelling and in addition, it really changed the tone of my conversations with patients. We spend our days talking to people and families about ALS and what it looks like, and now we can talk to patients with more hope. It's hopeful day; we're making a dent. We're just at the beginning of a new era in the discovery of new treatments and so we need to continue in this line of work and continue to do more research, more clinical trials, until we find cures for everyone who has ALS,” she said. “This is the first step.”

In her role, Paganoni has continued to follow and analyze the trial data, including new data from an Open Label Extension of the drug for those patients who participated in the clinical trial, who are continuing to take the medication longer term, giving Paganoni more insights into the drug's ongoing affects on ALS patients. She hopes to publish some of those results in the coming weeks, moving the FDA approval process one step closer to prove its function and capability to patients.

At this point, ALS treatment, she said, includes a combination of medications and therapy.

"ALS is a complex disease and if we look at other diseases that are complex, like cancer or HIV, or even heart disease, it's really combination treatment that works. There isn't any single drug or intervention that's a cure... we're not able to stop; we're not able to reverse the disease yet, but every positive trial result, such as this one, really brings us closer to having more options and really, ultimately, having a cure,” Paganoni said. “We're starting to develop new options to allow people to live better and that's just the start of it, and I hope that it is just the beginning of a new era in the discovery of new treatment for ALS."

Quick agreed that this could be just the beginning for more breakthroughs in ALS treatment.

"The bottom line was, the people who got the treatment, their progression or they’re worsening on that functional rating scale was slower than people who got the placebo,” said Quick, who was the director and investigator for the clinical trial at OSU, including some of his own patients.

While Klee and Cohen acknowledged that the effects could be different for each patient, what they saw in the trial and from its subsequent data from researchers like Quick and Paganoni, was that this drug could be the difference between “the ability to walk on your own or be in a wheelchair. It could be the difference between being able to feed yourself or needing a G-Tube,” Klee said. "I think the overall picture was that many patients kept their strength longer, kept them breathing longer.”

But, he said, they need to keep moving the needle forward on this drug.

“ALS doesn’t wait and we need better treatments, and what the data showed in our trial is that every day a person's on therapy, matters. It means that they keep their functioning and abilities longer — and that could mean all sorts of different milestones in someone’s life. I think, while it's exciting to have good data, at the end of the day, this is about people and families living with a really tough diagnosis that's been unanswered for far too long,” Klee said. “While we're excited, we now feel more of an urgency than ever that we need to get this to people."

"There are currently two FDA-approved ALS medications on the market that also show clinical benefits, including the one that Canter has been taking since his diagnosis. Rilutek (riluzole) was approved by the FDA in 1995 and Radicava (edaravone) was approved in 2017. Both have similar benefits to CENTUR AMX0035,"
Quick said. But together, he is optimistic that they could create a life-extending combination for patients.

"I'm hopeful that five years from now, we'll have, maybe a cocktail of different things that we can give to somebody. And maybe each of them works in a slightly different way and together, they can kind of be combined to be something that will have a significant benefit in slowing down the progression of the illness,” Quick said.

However, he said, there is not one single medication on the market that stops ALS completely — but, he continued, AMX0035 does have a different mechanism of action in terms of the way that it works in the body compared to the previous two medications.

"It has a different mechanism of action, so it works in a different way on the underlying pathology of ALS,” Quick said. “In a lot of ways, it's also similar to a lot of things we have right now — all of these medications work to slow down the progression of ALS. So, people who have ALS, even if we put them on these medications, they still get worse over time; the disease does still progress. But these medications slow down that process and delay it or spread it out over time, so that people on these medications stay at a higher level of function typically for a longer period of time, and it also delays that progression of the disease and helps people live longer."

"At this point, anything that clearly shows slowing of progression with ALS, would be considered breakthrough because if you look at the history of clinical trials for ALS for the last 30 years, lots of things have been tried... and found to be not effective,”
he said. “In a sense, that's sort of a big breakthrough in that this is one of three medications over that last 30 years that has been studied that clearly [shows] some benefit in slowing down the progression of the disease. It's a milestone."

Quick said, ALS treatment will require a “multi-faceted approach” for what he called a “daunting problem” they are facing.

"There's still a lot about ALS that we don't know and there's so many things going on in the nervous system with ALS,” he said. “I don't think it's going to be like one medication that you're going to be able to give to people and that's going to arrest the disease. It's just a really complicated illness... and if you think about the world of cancer, in cancer you're trying to kill cells. So you have these bad cancer cells you're trying to figure out something that's going to go into the body and kill those cells and make them dead, so that your cancer goes away. When we're talking about ALS, we're talking about trying to keep cells that are sick and trying to die and trying to keep them alive — and that's a much more challenging problem."

Paganoni concurs that AMX0035 is another strong tool for those combatting ALS and could be part of the right combination to save lives — something that she thinks could be right around the corner.

"These two options are a combination of medications to slow down the disease's progression, and in addition to supportive care, there are the first building block. Now, with this trial we are adding another tool, at least a promising tool — again it's still in investigation and we don't know if or when it could be approved, but it means that we are making some progress, that we are moving forward and I think that's hopeful for people with ALS,” she said. “Looking at the progress that we're making and looking at the fact that we're testing more drugs at a faster pace, I think really, the future is going to be brighter because we can make progress faster. We have a very cooperative, a very active research community."

"The pace is accelerated... it is the time to learn about ALS research [and] continue to do ALS research,”
she continued.



With extended research and more medications to treat the symptoms, and potentially slow ALS’s progression, Quick is confident that they are on the cusp of more medical breakthroughs — and that is, in part, thanks to this new treatment discovered inside a college dorm room.

"We're starting to see things in the pipeline of treating ALS that have a really good rationale for using them, and different medications that work on different aspects of the disease,” he said.

While there was a 25-year gap in breakthrough treatment, from 1990s and 2017, Quick said he hopes to see a new medication in research every year or two from here on out.

"I'm hopeful that we'll start to see this process of maybe every year, every other year, we start to find a new medication that has some effect on slowing down the progression. I'm hoping that's where this is going and it's not going to be another 20 years before we find something that's effective."

With that, he is hoping in the next five to 10 years, they will be able to offer a more effective combination of treatment for ALS patients.

"This was a success and it was really one of the first successes in a treatment looking at a disease like ALS which is a very difficult-to-treat, challenging, neurodegenerative condition that really showed an effect. Our understanding of the nervous system getting better and better, I think we're going to start seeing more and more things like this that are going to have some effect on these really difficult-to-treat neurodegenerative conditions, just as science gets better and we learn more about these illnesses,” Quick said. "I think it makes patients more hopeful when they see a lot of research is really being done very actively in this and that there's a lot of interest in it, and there's a lot of ongoing studies to be a part of. I think it does change the conversation quite a bit when I'm talking to people about this. It's still an incurable illness but it's not an untreatable illness.”

For the two guys who cooked up this idea in a dorm room, the results were something that they could never had anticipated.

"In ALS, trials have been going on for decades, and very, very, very few have been successful. So, I think whenever there is a successful trial in ALS, it's a big cause for celebration. I think it is a breakthrough against the disease,” Cohen said. "I kind of see this as just the beginning and hopefully the first drug of many that will continually make the quality of life and the state of this disease better and better. Unfortunately, steps like this have been few and far between and we are really excited that a breakthrough like this happened.”

"It was incredibly thrilling and kind of fulfilling and inspiring… but I think also a very heavy sense of responsibility that it's now on us to work closely with regulators and get this drug forward as fast as possible,”
Cohen said, who along with his partner, is working on federal drug approval through ongoing discussions with FDA and regulators worldwide, including in Canada, Japan and Europe.

For the inventors of this medication, it is important to maintain momentum because every second counts.

"We got all of the data at one moment at the end when the study was complete and getting that data's pretty thrilling — also, quite stressful. But we were over the moon when we saw it was positive,” Cohen said. “I think it pretty immediately also set in a pretty strong feeling of responsibly that once we have this data that patients with this rapid and progressive disease, really have no time to wait, and that every minute, every hour, that we're spending, we need to be spending to move it faster. We can't lose time at any juncture.”

While not a cure, perhaps one of the most notable breakthroughs is the optimism gained from the trial.

"I think the other thing is, this data injects a tremendous amount of hope into the field, and optimism, and I think that's really important because I think it reinvigorates all the research efforts that's going on. It gives a new handle and lens by which to understand the disease because we can ask, 'Why exactly did this drug work and are there insights we can take from that to treat the disease even better?'" Cohen said.

Not long after the trial, some of the researchers and staff threw a surprise party for Klee and Cohen, and one of the nurses walked over to them and told the pair something that has stuck with them.

She said, “My job every day is to talk with patients and families and tell them the worse news. I tell them they have a death sentence and I tell them how they can deal with it and I tell them what's going to happen and it's my daily job. I do that every single day; I've been doing that every single day for over 20 years. This is the first day, that I could tell them all there’s hope.”

"That was one of the moments where it really hit it home. It's easy for these things to be data on a page or science in a paper, but it really hits home when you realize that every data point, every statistic are people when you're going through this. So, I felt incredibly humbled, and definitely feel a big responsibility going forward,”
Cohen said. “There's progress. There's hope."

With the success in ALS treatment, Klee and Cohen, co-founders and co-CEOs of Amylyx Pharmaceuticals, believe that their “breakthrough” medication, CENTUR AMX0035 could be a proof of concept for other diseases, and they hope to get more studies up and running in those areas as well.

"The goal of the therapy was intervene in the neurodegenerative process, so it's not necessarily specific to ALS,” Klee said. “We think that the drug could benefit in any disease where neurodegeneration is an issue, and there are many of them, Alzheimer's, Parkinson's, Huntington’s.”

Quick believes, thanks to AMX0035, this could be just the beginning for more medical breakthroughs.

"I think that neurological diseases are one the next big frontiers in medical science because they are challenging and for a long time it was a tough target to go after. I think we're understanding so much more about the nervous system than we did in the past but I think with the right resources, I think we're going to be able to learn a lot more and be able to come up with things that are not just going to be better for treating ALS but be better for treating things like Parkinson's disease and Alzheimer's disease and Huntington's disease and Multiple Sclerosis, so I think we're kind of at the cusp of, what is hopefully, an explosion of new treatments and better understanding of these neurological conditions that have been historical hard to manage and treat,” Quick said.

In fact, the drug is currently in a clinical trial for Alzheimer's and Cohen and Klee continue to evaluate a number of other neurodegenerative diseases that could benefit from this therapy as well. In the next year, they are hopeful that their Alzheimers trial data will be released, in which they are using the same dose of AMX0035 with a 100 participants.

But as for ALS, while it may not be a cure, it is the next step towards that four-letter word.

"I think what's easy to forget sometimes, is that we all want cures and that's what we need to work towards. But if we look at the development in diseases like, HIV, cancer, the first therapies weren’t cures, but they were breakthroughs. They said, 'We can treat this thing.' And now, look where we are. I mean, diseases that were death sentences are now being treated as chronic diseases and sometimes can be true cures. That's what we want in ALS, too," Klee said. “This isn’t a cure, but we do think it’s a breakthrough. And the reason I wouldn't say, ‘miracle,’ is because like all things in medicine, you have to ground things in really deep science. And we were so fortunate that we had this good idea but then we had some real leaders in science and medicine help us to get to this point. I think the biggest takeaway is that the drug benefited people. We tested it in the best clinical centers in the country and we ran a really rigorous trial and the drug showed benefit. It's not a cure but it's a big step forward and we hope it's just the start.”

Cohen agreed.

“I think this is a really hopeful time in ALS," Cohen said. "We're hoping that the landscape of this disease and the shape of this disease changes rapidly over the coming years."

Their drug has already changed the landscape for one man: Canter.

"Us, who's suffering from ALS, we're not looking for a cure right now,” he said. “Before you have a cure, you have to have treatments. I'm lucky, because I was in the trial, but there's thousands suffering with nothing."

And he wants to help be the voice for other patients who are suffering from the terminal disease — in hopes that one day, the word, “terminal,” can be dropped from its diagnosis.



Following the 24-week clinical trial, Canter was given the option to join the Open Label Extension trial for the drug, giving him the opportunity to knowingly take CENTAUR AMX0035 for researchers to study the long-term impact of the drug.

Since Canter started taking the drug regularly outside of his initial trial phase, he said that he has already noticed the progression of his ALS symptoms change.

"I started noticing my breathing pattern... it drastically slowed down my progression in my breathing pattern — in my lungs, my diaphragm," he revealed.

However, his extremities, like his hands, arms, legs, have steadily gotten weaker.

"I'm not saying I'm getting better, but that shows me that my breathing, which you have to have to live, has really seen a positive reaction to this medicine, drug I'm taking,” he said.

Like Canter, 90 out of the original 137 participants have opted to continue into the Open Label Extension, giving him and others something that they never thought was possible with ALS: hope.

"One thing you have to have in life is hope. And this medicine gives me my hope right now,” Canter said. “There's hope right around the corner."

He will be guaranteed the medication from the trial, he said, until May 2022.

But the early idea he had of gaining one more day, or even a few more months to live, when he was first diagnosed, has since changed.

"I want years,” he said. "I think if it wasn't for this drug, I would be in the ground today. I think this drug is keeping me above ground as we speak."

But waiting on the FDA to approve the drug he believes has helped him already, frustrates Canter.

"In 2020, with all the help that's out there, these people that are dying today, should still be alive tomorrow, point blank. Give us the help that we need. The help is out there. It's not fair,” he demanded. "Give us access to these treatments. ALS isn’t what’s killing us. ALS isn’t the battle; it’s getting these approved and accessable to all.”

While Canter said ALS has long-been known as the “cry-and-die” disease, he refuses to give into that theory and plans on fighting for his life.

Acknowledging that you seldom hear of success stories with ALS, Canter said that he is determined to be one of those rarities.
Unlike most ALS patients, Canter has not yet lost his ability to speak. And he uses that to the fullest, not only for himself, but to amplify his voice on behalf of anyone else battling this disease.

"I'm lucky to still have a voice. So many people with ASL don't even have a voice anymore," he said. "So, when I speak, I speak for them, for the ones who can't talk."

While there is no cure for the fatal disease, Canter has something he never thought possible back in 2018 when he was first diagnosed.

"You have to keep hope. We've got help right around the corner. You can't give up," he said. "All these people are suffering... and in a matter of one day, something could be changed."


Bucket list and blessings

Sitting inside his quaint white house, situated on a slight hill in his small, rural town in Brown County, Canter grips tightly to his independence for as long as he can. In the kitchen, next to a Cincinnati Reds face mask, sits a large, blue pill box inside a woven basket, filled to the brim with his medications for the day.

The man who once considered himself a healthy athlete, is now confined to his recliner next to his front picture window, where we watches the world moving on around him — neighbors going about their daily lives — driving to work, doing yard work, enjoying life. Next to him, on a wooden T.V. tray, is a container of his afternoon medications in small cups and pouches that his mom has put together for him because he cannot do it himself.

“If you would've asked me two years ago what paralysis feels like, it was nothing like what I'm experiencing. I always thought that like, your mind has control of your body to where you could look at hand and say, 'Open up, hand!' It's attached to you and how it's all attached to your brain, and no matter how hard it is, you can always get them open. Well, it doesn't work that way. Like, my right thumb is dead. I've got nothing in my right thumb — I can't bend it or nothing, no feeling. It's like it's not even attached to me anymore,” Canter said.

It is a frustrating obstacle, but he has learned to overcome what his body can no longer do.

"You learn to cope. You learn to adjust your life,” the once-avid hunter said, sitting in his living room where two of his prized deer trophies are proudly mounted on the wall behind him.

“You learn to adjust your abilities and you live today with what you're given. I'm just so thankful that I'm here."

To further cope, he likes to remember that “blessings still happen every day,” he said wearing a camouflage trucker’s ball cap, donning an American flag.

One of those blessings is just outside.

In his slanted driveway, sits a handicap-accessible van — but on the other side of his two-car garage door is his ticket to the outdoors and his independence.

As the motorized door rolls up, a polished, but dusty, bright yellow Corvette sits parked. He has not taken that out for a ride in more than a year. These days, he revs up a different ride for cruising, his scooter — and it has made all the difference for him and given him the ability to feel the fresh air on his face and the wind in his hair.

"You sit inside here, this is what kills people. Sitting in a chair in a quiet house, alone, where your mind races and tries to wonder off on you. That's what kills you,” Canter said. “Being outside and become active, and even with my abilities, I still like to ride my scooter."

His dad helps him onto his scooter, but once he is perched on his three-wheeled Harley Davidson scooter that tops out at 12 m.p.h., he has a 45-mile range to ride freely.

"Fourteen miles, one day I rode it. That's my mind therapy. When I can do things outside, that's a huge bonus, a huge help — keeps me from thinking,” Canter said.

According to the ALS Association, someone is diagnosed with the ALS every 90 seconds. Johns Hopkins Medicine estimates that disease is responsible for as many as five out of every 100,000 deaths.

"We're all dying. In a way, we're all terminal... in reality, nobody knows what your expiration date is; everybody's got one,” Canter said. “From the beginning, it's a life sentence when they give it to you. You know you're not going to have much of a future left.”

But he was determined to make the most of his life, regardless of his “expiration date.”

When he was first diagnosed, he remembered, his doctors told him, "My future is now. If I have a bucket list, work on bucket list now… basically, you're living for today. If there's anything in life you want to accomplish, do it now, while you can. That's how everybody should be living anyway. Nobody's guaranteed tomorrow."

For him, that started with taking in every Reds baseball game he could — which led to a pretty special day at Great American Ballpark last year.

On May 5, 2019, the Cincinnati fan was named the captain of a home game against the San Francisco Giants. Even though he could not throw out the first pitch, he did take the starting lineup to the pitcher's mound, where he was announced and his story about ALS was told to the fans, who, in turn, gave Canter a standing ovation.

"It was a very neat experience,” he said, remembering it only by watching video from the day, because he was too awe-struck from the sheer excitement of it all.

Continuing his bucket list and his Reds-fandom, Canter took a road trip following the team’s season, traveling to ballparks in Milwaukee and Chicago. Along the way, he met several Reds' players and still keeps in touch with them today.

"I've had so many people come into my life because of this illness, that I could have easily just kept my eyes shut and my heart shut and not let them in my life — and that has been so valuable in the past two years to me,” Canter said.

He keeps them close these days because, he said, he gains power and immeasurable strength from those around him.

“When you surround yourself with negativity, you're going to become a negative person,” Canter surmised. “When you surround yourself with positive people and positive influences, you become a positive person; it's contagious.”

From that positivity, he builds up his own motivation to power through and overcome ALS or whatever comes his way.

"Inspiration and motivation is a power that you build inside of you. It's not given to you, you have to find it,” he advised to anyone struggling.

And Canter is inspired to keep moving, however he can, and counts his blessings for the treatment that has already shown signs of promise.

“No matter how bad ALS is, there's still blessings that happen every day,” he said. “You just have to have your eyes and your heart opened up to see it and accept it.”

The ALS Association has a petition online for FDA approval for the drug, AMX0035. To learn more about ALS, donate to ongoing research and to sign the petition, visit https://www.als.org.

 
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Medicare-for-all activist's emotional appeal for Universal Healthcare*

by Ady Barkan | Democracy Now! | 18 Aug 2020

Hello, America. My name is Ady Barkan, and I am speaking to you through this computer voice because I have been paralyzed by a mysterious illness called ALS. Like so many of you, I have experienced the ways our healthcare system is fundamentally broken — enormous costs, denied claims, dehumanizing treatment when we are most in need.

Since my shocking diagnosis, I have traveled the country meeting countless patients like me, demanding more of our representatives and our democracy. Today we are witnessing the tragic consequences of our failing healthcare system.

In the midst of a pandemic, nearly 100 million Americans do not have sufficient health insurance. And even good insurance does not cover essential needs like long-term care. Our loved ones are dying in unsafe nursing homes, our nurses are overwhelmed and unprotected, and our essential workers are treated as dispensable.

We live in the richest country in history, and yet we do not guarantee this most basic human right. Everyone living in America should get the healthcare they need, regardless of their employment status or ability to pay.

Even during this terrible crisis, Donald Trump and Republican politicians are trying to take away millions of people’s health insurance. With the existential threat of another four years of this president, we all have a profound obligation to act — not only to vote, but to make sure that our friends, family and neighbors vote, as well.

Each of us must be a hero for our communities, for our country. And then, with a compassionate and intelligent president, we must act together and put on his desk a bill that guarantees us all the healthcare we deserve.


 
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Antiepileptic drug reduces motor neuron excitability in ALS

Mass General | Neuroscience News | 10 Dec 2020

Ezogabine, an antiepileptic drug, reduces the excitability of cortical and spinal motor neurons associated with ALS.

The antiepileptic drug ezogabine reduced pathologic excitability of cortical and spinal motor neuron cells that are early signs of clinical dysfunction in people with amyotrophic lateral sclerosis (ALS), according to a study conducted by the Neurological Clinical Research Institute of Massachusetts General Hospital (MGH).

In addition to providing a clearer understanding of motor neuron excitability as an important disease pathway for ALS, the multi-site study, published in JAMA Neurology, involves the first clinical investigation of ALS (also known as Lou Gehrig’s disease) using a drug identified through an induced pluripotent stem cell (iPSC) model.

“The stem cell approach allowed us to capture the hyperexcitability of motor neurons — a prominent disease phenotype — and to then show ezogabine was able to reduce it in people with ALS,” says lead author Brian Wainger, MD, PhD, of the Healey Center for ALS at MGH. “Our findings could have important implications for the field of ALS research both by demonstrating the effect of ezogabine on excitability in people with the disease and by showing that the metrics of cortical and spinal motor neuron excitability may be used as drug biomarkers in multi-site clinical trials.”

ALS is a progressive neurodegenerative disorder that leads to the death of neurons in the brain and spinal cord that control speech, swallowing and limb movements. Named after the famous baseball player Lou Gehrig, who was diagnosed with the disease in 1939, there are around 20,000 people in the U.S. with ALS, and another 5,000 newly diagnosed cases each year. Currently, there are three approved drugs in the U.S. for treating ALS, each with limited benefit, creating an urgent need for new therapies that could change the course of the fatal disease.

The MGH study of ezogabine was not designed to assess the long-term effects of the drug on the neurodegenerative disorder, but rather to unravel the biological processes that go awry and identify novel molecular targets for drug intervention. To that end, the ten-week, phase 2 study of 65 participants with ALS at 12 U.S. sites investigated the feasibility of using neuron excitability metrics as predictors of disease progression. “We demonstrated for the first time that these neurophysiological assays can be effectively deployed across multiple study sites, which is important in trials of diseases like ALS where investigators rely on many sites for recruitment,” explains Wainger. “That finding could be useful in evaluating other drugs to treat ALS, or even for other diseases where motor neuron metrics could serve as key biomarkers.”

Ezogabine (also known as retigabine) had been previously approved by the U.S. Food and Drug Administration (FDA) for treating epilepsy with a unique mechanism of action: facilitating potassium channels in cell membranes that play a central role in controlling neuron excitability, particularly important in the control of seizures. Researchers from MGH’s Neurological Clinical Research Institute began evaluating the drug’s potential in the context of ALS, using transcranial magnetic stimulation (TMS) and threshold tracking nerve conduction studies (TTNCS) to measure the effects of ezogabine on motor neuron excitability. They learned that ezogabine did indeed calm the excitability of motor neurons.

“Further studies are needed to determine if longer treatment will sustain the effects of reduced excitability and, if so, whether that may slow disease progression,” says Wainger. “Through our study we’ve hopefully established a new research paradigm for using iPSC-based in vitro models for identifying novel disease targets and compounds, and rapidly repurposing drugs for clinical trials.”

 
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Scientists identify compound to reverse neuron damage from ALS*

Northwestern University | Neuroscience News | 23 Feb 2021

U-9, a novel, non-toxic compound, targets upper motor neurons and reverses damage associated with ALS within 60 days of treatment.

Northwestern University scientists have identified the first compound that eliminates the ongoing degeneration of upper motor neurons that become diseased and are a key contributor to ALS (amyotrophic lateral sclerosis), a swift and fatal neurodegenerative disease that paralyzes its victims.

In addition to ALS, upper motor neuron degeneration also results in other motor neuron diseases, such as hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS).

In ALS, movement-initiating nerve cells in the brain (upper motor neurons) and muscle-controlling nerve cells in the spinal cord (lower motor neurons) die. The disease results in rapidly progressing paralysis and death.

So far, there has been no drug or treatment for the brain component of ALS, and no drug for HSP and PLS patients.

“Even though the upper motor neurons are responsible for the initiation and modulation of movement, and their degeneration is an early event in ALS, so far there has been no treatment option to improve their health,” said senior author Hande Ozdinler, associate professor of neurology at Northwestern University Feinberg School of Medicine. “We have identified the first compound that improves the health of upper motor neurons that become diseased.”

The study will be published in Clinical and Translational Medicine on February 23.

Ozdinler collaborated on the research with study author Richard B. Silverman, the Patrick G. Ryan/Aon Professor of Chemistry at Northwestern.

The study was initiated after Silverman identified a compound, NU-9, developed in his lab for its ability to reduce protein misfolding in critical cell lines. The compound is not toxic and crosses the blood brain barrier.

The NU-9 compound addresses two of the important factors that cause upper motor neurons to become diseased in ALS: protein misfolding and protein clumping inside the cell. Proteins fold in a unique way to function; when they misfold they become toxic to the neuron. Sometimes proteins aggregate inside the cell and cause pathology as in the TDP-43 protein pathology. This happens in about 90% of all ALS patient brains and is one of the most common problems in neurodegeneration.

The research team began to investigate whether NU-9 would be able to help repair upper motor neurons that become diseased due to increased protein misfolding in ALS. The results in mice were positive. Scientists next performed experiments to reveal how and why the diseased upper motor neurons regained their health.



New compound restores neurons to robust health

After administering NU-9, both the mitochondria (the cell’s energy producer) and the endoplasmic reticulum (the cell’s protein producer) began to regain their health and integrity resulting in improved neuron health. The upper motor neurons were more intact, their cell bodies were larger and the dendrites were not riddled with holes. They stopped degenerating so much that the diseased neurons became similar to healthy control neurons after 60 days of NU-9 treatment.
“Improving the health of brain neurons is important for ALS and other motor neuron diseases,” Ozdinler said.

Upper motor neurons are the brain’s commanders-in-chief of movement. They carry the brain’s input to spinal cord targets to initiate voluntary movement. The degeneration of these neurons impairs the connection from the brain to the spinal cord and leads to paralysis in patients.

Lower motor neurons have direct connections with the muscle, contracting muscle to execute movement. Thus, the lower motor neuron activity is in part controlled by the upper motor neurons.

Ozdinler and colleagues will now complete more detailed toxicology and pharmacokinetic studies prior to initiating a Phase 1 clinical trial.

*From the article here :
 
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