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mr peabody

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Lyme disease and ALS

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is one of the most devastating diseases of our modern era, but new research is showing that the disease may have a trigger that was not realized before, Borrelia burgdorferi, the bacterium responsible for Lyme disease.

ALS causes gradual motor neuron death, hence its classification as a neurodegenerative disease. It is estimated that at least 20,000 people in the U.S. suffer from this condition and the average life expectancy only is 2-5 years following a diagnosis, although about 25% of patients live longer than 5 years. Thanks to funds raised from the Ice Bucket Challenge in 2014, researchers have discovered a new genetic contributor –a gene called NEK1. While identifying genetic contributors may help lead to more effective treatments, it is only one piece of the puzzle. As the saying goes, “genes load the gun, environment pulls the trigger.” Ignoring the “triggers” limits treatment options, hinders preventative measures from being explored, and over-simplifies the complexity of chronic disease. One of the triggers that has been implicated in ALS is chronic infection with various pathogens, one example being B. burgdorferi – the bacterium responsible for causing Lyme disease.

Although this finding and its clinical implications are controversial, it deserves attention for a couple of reasons. For one, misdiagnosis is serious business, especially when recovery rates are higher for the disease being overlooked than for the one being given (Lyme disease is more treatable than ALS). There have been several case reports of patients who were misdiagnosed with ALS – with or without meeting all the criteria for ALS – who went on to test positive for Lyme disease and subsequently improved following antibiotic treatment. Left untreated, Lyme disease can infect and cause damage to the central nervous system. CNS infection with B. burgdorferi is known as neuroborreliosis. Symptoms of Lyme disease and ALS can be overlapping, particularly in the early stages of ALS. These include muscle pain or weakness, muscle twitching or cramps, loss of coordination, poor concentration or other cognitive changes, and behavioral changes such as irritability.

Another reason the link between Lyme disease and ALS should not be ignored is that there are multiple studies documenting the presence of certain bacterial, viral, and fungal infections in ALS patients. It is not just speculation. A review article published just this year in Current Topics in Medicinal Chemistry mentions the Halperin study, which found that 50% of ALS patients tested positive for B. burgdorferi compared with 10.5% of controls. On the other hand, a larger-scale study published this year in the European Journal of Neurology found no association between borrelia antibodies and ALS. However, one of the main problems with this study (and others that seek to disprove a possible link), employ testing methods (antibody testing) that do not definitely rule out the presence of the bacteria. Accuracy is largely dependent on the patient mounting a proper antibody response and yet chronically ill patients often have immune dysregulation that results in antibody responses that do not follow the normal pattern. There are also other concerns with this type of testing, which goes beyond the scope of this article. DNA-based testing, such as polymerase chain reaction (PCR) methods are much more accurate. This same review article includes a case study of a patient with an ALS-like illness who tested positive for Lyme disease using PCR.

It is worth noting that other infections have been linked to not only ALS, but also to other neurodegenerative diseases such as Multiple Sclerosis and Alzheimer’s disease. It is well-established that pathogens can cause neurodegeneration via the deposition of misfolded protein aggregates, oxidative stress, deficient auto-phagic processes, synaptopathies, and neuronal death. The authors of the review article postulate that these mechanisms combine with things like aging, metabolic disease, and genetics to trigger a neurodegenerative disease. Even if these infections are more opportunistic than they are causative, they are still linked to morbidity and the progression of disease and therefore should be addressed.

Layperson analyses, case reports, and anecdotal stories have brought to light other fascinating arguments regarding the relationship between geographical patterns of the occurrence of Lyme disease being similar to that of ALS and stories of recovery from ALS when treated for Lyme. Meanwhile, the research is still trying to catch up. Many government agencies and physicians have been quick to dismiss the link between ALS and Lyme disease. This is unfortunate since the best researchers and clinicians are those who keep an open mind and thoroughly investigate all avenues. If ALS is essentially a death sentence, don’t we owe it to those suffering to spend research dollars investigating all the proposed mechanisms and the possible interplay between them? We think so!

https://www.holtorfmed.com/borrelia-burgdorferi-found-in-als-patients/
 
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mr peabody

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First U.S. patient to get new ALS drug passes away, but he's still fighting to help others

When a local man became the first person to get a new drug to treat ALS, he became the symbol of hope for everyone with the disease.

Sadly, the treatment ended up not working for him. However, even in death, he’s still fighting to help others just like him.

Rene Fogarty made medical history as the first person in North America to receive Radicava, the first new drug in two decades for ALS, or Lou Gehrig’s disease.

He died last month at the age of 53.

“We thought the end is coming, because he was having trouble breathing, but we never thought it would happen so fast,” Linda Fogarty said.

“Usually, it’s the respiratory function that fails,” Dr. Sandeep Rana, of Allegheny Health Network Neurology, said.

Rene worked until the end, sitting at his computer. But eventually, he had trouble.

“Two weeks before he passed, he said to me, ‘You know, I’m not going to work today. I don’t feel well.’ And he was losing his breathing,” Linda said. “I told his boss, that if he stops working, that’s when he’s going to go. And I was right. Two weeks later.”

To help with communication, Rene used a device controlled by eye movements. Linda says he still made jokes that way, even when his muscles were too weak for speaking.

“Never, never lost his sense of humor,” she said.

At a celebration of Rene’s life, his family, coworkers, bosses, neighbors, and friends gathered for his favorites — hot dogs, tres leches, ham and cheese sandwiches, and a toast.

“And everybody actually, took a little sip of scotch, just in your name, Rene,” Linda said.

Rene donated his organs, and his brain.

“People will be able to walk and see because of him. And hopefully this brain donation gets them closer to a cure,” Linda said.

While Linda admires Rene’s altruism, she’s not so sure about the new drug.

“The average is two to five years. He left us in a year and a half,” she said.

The drug is covered by insurance, but the home visits and the medical supplies are a costly out of pocket expense.

“Initial four to six months, I felt the medication was helping. It was stabilizing him. But thereafter, he did progress,” Dr. Rana said.

Rene decided to stop the treatments at his final doctor visit. Two weeks later, he died.

“He was struggling, but I still felt he had few more months,” Dr. Rana said. “The end came suddenly. We were all saddened and taken aback.”

“It’s a horrible disease. And you never know who’s going to get it,”
Linda said. “He said, ‘Always remember my life. Not my death.’

https://pittsburgh.cbslocal.com/2018/12/26/first-us-patient-als-drug-passes-away/
 
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mr peabody

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Researchers identify a potential new drug target for ALS

Did you know that there is a protein known to be affected in 97% of all ALS cases? This has led researchers to investigate the protein TDP-43 to learn more about its interactions within cells and how these interactions could contribute to disease. As a result, two research groups have independently identified a protein called STMN2 as playing a role in ALS. Both groups published their findings in the February 2019 issue of Nature Neuroscience.

In a study led by researchers from Harvard, scientists used motor neurons derived from stem cells to investigate what happens when TDP-43 clumps together and is no longer able to function properly, as seen in most ALS cases. The researchers analyzed a variety of interactions within cells, and found that one in particular stood out. They found that when the amount of functional TDP-43 was decreased, the level of another protein, STMN2, also decreased substantially. STMN2 is known to play a role in the growth and repair of motor neurons.

In the second study led by a team from the University of California at San Diego, patient tissues were analyzed by researchers who found that STMN2 levels are lower than expected in motor neurons from the brains and spinal cords of ALS patients with and without a family history of the disease. Also using motor neurons derived from stem cells, the researchers tested whether increasing the levels of STMN2 could help to restore motor neuron health and found that it did have a restorative effect.

Taken together, these studies suggest that STMN2 could represent a potential new biomarker for ALS, which is important for earlier and accurate diagnosis. Further, drugs designed to restore the natural levels of STMN2 in cells represent a promising new treatment avenue for researchers to explore.

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Insights from the body’s natural immune response open up new treatment avenues for ALS

Researchers from Université Laval and the CERVO Brain Research Centre have generated a specialized antibody, called a single-chain antibody, that helps to correct an abnormal behavior of TDP-43, a protein known to be affected in almost all ALS cases. Antibodies are proteins that are produced by the immune system to protect the body against foreign invaders like bacteria and viruses, and work by binding to specific proteins on harmful agents and triggering their removal and/or destruction. Antibodies, however, are also commonly used as tools within the laboratory. For example, antibodies can be designed to bind to specific proteins in cells allowing researchers to visualize where and how much of the target protein is within the cell.

In a February 2019 study, researchers set out to harness the power of single-chain antibodies to battle ALS and developed one that could specifically target TDP-43. To test the effectiveness of the antibody, the researchers inserted the genetic material that directs production of the antibody into a virus that was then injected into the spinal canal of mice with ALS. This allowed the single-chain antibodies to be made inside cells, where TDP-43 is found, allowing them to have more of an effect compared to traditional antibodies that generally cannot pass through the outer barrier of cells. The results showed that when mice were treated with the antibody, the number of toxic TDP-43 clumps in cells was reduced and the mice displayed increased cognitive and motor function compared to controls (i.e. ALS mice not treated with the antibody). The results from this preclinical study support future development of immunotherapy techniques for the treatment of ALS.

 
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Transplant of human neural stem cells into ALS patients found safe

by Patricia Inacio | May 23, 2019

Injection of human neural stem cells into the spinal cord of people with Amyotrophic Lateral Sclerosis was found safe and did not cause adverse effects even two years after the transplant, results from a Phase 1 clinical trial show.

Human neural stem cells are able to integrate brain tissue and promote tissue regeneration. These cells have shown potentially beneficial effects in preclinical animal models of neurological diseases, but very few studies have assessed its feasibility in human patients.

The Phase 1 trial evaluated the safety (as its main objective) and feasibility of injecting human neural stem cells into the spinal cord of ALS patients.

Researchers isolated human neural stem cells from two miscarried human fetuses, which were then expanded in the lab prior to injection.

“Our study is the first to use medical transplantation of stable, clinical‐grade hNSC lines that are isolated from brain biopsies from fetuses that are miscarried, and that can be reproducibly and stably expanded ex vivo,” the researchers wrote.

The trial included 18 ALS patients, five women and 13 men, with a median age of 48 years. Patients were followed for a median of 24 months after the cells were implanted.

During this period, no patients reported severe adverse effects, and only one patient reported mild painful spasms in the lower limbs. A common adverse effect was pain after surgery, but was confined to the implant site and lasted 18 days on average.

“Our results underscore that micro-transplantation of cells into the human anterior spinal cord is a safe procedure, even in subjects as fragile as patients with ALS,” the researchers wrote.

Imaging analysis using magnetic resonance showed there was an expected accumulation of extradural fluid at the surgery site that was resolved spontaneously within three to six months. No structural changes were observed for the brain and spinal cord of patients compared with images at the start of the study.

From the initial group, 11 patients died during follow-up due to the natural progression of ALS disease. Two patients underwent a tracheostomy due to progressive respiratory failure.

According to researchers, the treatment did not worsen the ALS progression in any patient. They did detect a temporary slowing of disease progression as shown by stabilization in some patients and improvement in others of scores on the ALS Functional Rating Scale Revised within the first month after transplant, continuing for up to four months.

Moreover, five patients reported a transitory functional improvement in ambulation and four patients in activities such as cutting food and handling utensils, handwriting, dressing, and hygiene. No statistically significant differences were detected in the forced vital capacity, a measure of lung function, nor in survival.

These results support the need to further assess the potential of human neural stem cells in a Phase 2 trial to continue to assess the cell’s safety as well as its efficacy.

“Our results support the use of [good manufacturing practice]-grade fetal hNSCs derived from in utero spontaneous death in future efficacy-seeking clinical trials for treatment of ALS,” the researchers wrote.

However, “substantial challenges remain to be addressed and resolved in upcoming phase IIa/IIb trials, including determination of the optimal number of cells to be injected, how long the cells remain active in humans, the criteria for patient selection, biomarkers for monitoring the disease course, and efficacy of the hNSCs,” they concluded.

 
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mr peabody

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ALS patients' clear message: “NO MORE EXCUSES”*

by Nicholas Florko | STAT+ | June 7, 2019

Next Wednesday, a cadre of ALS patients will gather for a protest outside the FDA’s headquarters in suburban Maryland with a clear message: “No More Excuses.”

The rally is being organized by a ragtag group of ALS patients who connected mostly through Facebook, and it’s far less a production than other efforts like the 2014 ice bucket challenge that swept around the world.

These protesters haven’t even established a formal organization or a website; some said they’ve never even been to a protest. There’s nary a poster board in sight, yet.

But the band of patients is already catching the attention of regulators at the Food and Drug Administration, establishment advocates at the ALS Association, and top bioethicists around the country. Top Senate lawmakers, too, are beginning to advocate for their cause.

These protesters say, at least, that they plan to emulate the aggressive, even “radical” approaches and the take-no-prisoners strategy of the AIDS activists who protested the FDA’s slow work on that disease in the 1980s. Like the ACT UP activists before them, the ALS patients are coming armed with a list of specific therapies they want regulators to approve — and fast. But unlike their predecessors, they’re hoping not to be arrested next week.

ALS patients are fed up

They’ve seen no results from their advocacy for the national “right-to-try” law that promised access to new cures. And they’ve felt left out as the FDA approved treatments for other similarly fatal neuromuscular diseases.

“We as ALS patients are just tired of no action being taken on our part,” said Mike Henson, one of the organizers. “I don’t know what’s worse, getting ALS 10 years ago and just knowing you’re going to die, or getting it now and knowing that you could be saved if only people would take this seriously.”

Henson lives in Tulsa, Okla., and was diagnosed with ALS last year. He is a former logistics manager for a rock casino who speaks his mind, calling ALS “a murderous disease.’’ He’s made a name for himself in the ALS community by starting his own ALS talk show on YouTube, complete with a chyron and green screen.

Just Wednesday, the protesters adopted a name for their troupe: “Contagious for a Cure.”

And there’s a specific potential cure they’re seeking — or rather, three. A trio of drug companies is in the middle of the development process for separate, still-investigational ALS drugs: BrainStorm’s stem cell treatment NurOwn, Collaborative Medicinal Development’s synthetic molecule CuATSM, and Dr. Stanley Appel’s cell therapy known as Tregs.

The drugs are all at quite different stages of clinical development: BrainStorm is currently enrolling a Phase 3 clinical trial, Collaborative Medicinal Development has only completed Phase 1 testing, and Appel’s Tregs has only been studied in three patients.

ALS patients have demanded access to BrainStorm’s NurOwn throughout the fight for a federal right-to-try law. So much so that the company’s CEO Chaim Lebovits promised that patients would be able to access the drug once right to try was law, only to largely go back on that promise and instead provide access to only one right-to-try activist, Matt Bellina.

Henson and his fellow organizers want to know why these drugs aren’t being fast-tracked through the FDA’s approval process, especially while drugs for other neuromuscular diseases are being approved, seemingly left and right. He points to Zolgensma, Novartis’ gene therapy for spinal muscular atrophy, which was approved based on a trial of only 15 children — albeit with impressive results.

“That drug was approved very quickly with a very small trial,” Henson said. “So, we know this can be done, if we have the will to do this.”

The FDA said it “stands ready to help” the ALS community — including by helping patients and their doctors evaluate options like clinical trials or using the FDA’s expanded access program to get ahold of experimental, unapproved treatments. A spokeswoman also said the agency “is prepared to use all expedited development and approval programs at its disposal” to make new treatments available.

Two top officials in the agency’s drug approval centers, Janet Woodcock and Peter Marks, also offered to meet with advocates and drug makers next week, so long as the drug makers would also participate.

“We encourage you to reach out to each of the manufacturers to request a meeting with the agency that includes you and any other members of the ALS community that you would like to include. With their permission, we welcome the opportunity to have a transparency discussion about their investigational products,” Woodcock and Marks wrote in an email shared with STAT.

More and more, cries for more progress are coming from Capitol Hill as well. Republican Sens. Ted Cruz (Texas), Marco Rubio (Fla.), Mike Braun (Ind.) and Mike Lee (Utah) wrote to acting FDA Commissioner Ned Sharpless last month making a similar demand.

The senators are calling for the FDA to bring back the so-called parallel track that the agency unveiled for AIDS patients in the 1990s. Under that pathway, which was never extended beyond HIV and AIDS patients, those ineligible for clinical trials could gain access to certain drugs still being studied. It’s estimated that thousands of AIDS patients got access to one such drug, Stavudine, under the parallel track in the 1990s.

“It is time for the FDA to create and encourage an environment that promotes patient choice, patient access, and patient affordability,” they wrote. “Expansion of the Parallel Track is a proven solution to do just that, and we strongly encourage the FDA to act immediately on this issue.”

It’s a perplexing request. In the years since it created the parallel track, the FDA has stood up several more concrete pathways for patients to access experimental drugs.

The FDA isn’t the only target of these protesters. The group also plans to protest the ALSA. They want answers as to why the $115 million raised by the ice bucket challenge hasn’t gone to fund development of their three favorite potential therapies. ALSA has technically funded two of the therapies, although the protestors insist their funding was not nearly enough.

“What we just can’t figure out is why ALSA is not vigorously pursuing getting any of these drugs into our bodies immediately!” the organizers of next week’s protest wrote to ALSA.

They’re so frustrated with ALSA that they’re calling for the resignation of the group’s President and CEO Calaneet Balas.

In a statement to STAT, ALSA said it was “working urgently to end ALS,” which includes funding “many early stage clinical trials and work[ing] with the FDA and scientists to help trials run faster.” An ALSA-sponsored report released Tuesday also found that the ice bucket challenge resulted in ALSA increasing its research funding by 187%. Among the achievements from that research: discovery of five new genes potentially tied to ALS.

But the protestors want more specific commitments from ALSA to work with BrainStorm, Appel, and Collaborative Medicinal Development “with the ultimate goal of having any of these viable therapies available to the ALS community within the next 6 months maximum.”

Henson is convinced these three treatments — either alone or in some combination — are the cure for ALS.

“They’ve been PROVEN,” he insists.

But experts aren’t so sure.

“These people are desperate, I can see that. I see them every day. ALS is a horrible disease,” said Dr. Jonathan Glass, the director of Emory University’s ALS Center. “But fast-tracking things that don’t work, or may not work, or might even be harmful is not the way to go.”

Glass argues some of the treatments these patients have latched onto show promise. He had particularly kind words for Appel’s theory, but he insisted it was far too early to allow access to any of these drugs. He also strongly disagreed that any parallels could be made to Novartis and subsidiary AveXis’s Zolgesma, or even the more controversial Biogen drug Spinraza.

“This is not what we are seeing,” Glass said. “The reason AveXis and Biogen can get their drugs approved is you take a universally fatal disease and you actually not only stop it from being fatal, but you watch these kids get better. If we had a drug like that for ALS, great, let’s approve it. But we don’t, and none of those drugs are going to do that.”

And Glass isn’t the only one increasingly uncomfortable with next week’s protest.

To the organizers of next week’s protest, former ACT UP members like Gregg Gonsalves, are celebrities.

“They (ACT UP) are definitely our role models,” said Annie Swartz, another organizer of next week’s protest. “They showed us how to kick ass, and how to get treatment, and how to speak for those that might not be able to speak for themselves.”

But that’s an uncomfortable comparison for Gonsalves, who is now a professor at Yale and a MacArthur Genius Fellow. Now 30 years removed from the day ACT UP stormed the FDA’s campus, Gonsalves maintains that the group’s early anger toward the FDA was misdirected.

He laments the fact that the group’s message has been co-opted by groups urging deregulation at the FDA. He fears that pushing the FDA to allow access to largely unproven treatments will stifle the research that could eventually lead to a cure for ALS and countless other fatal diseases.

But Gonsalves also understands the anger, pain, and most importantly the relative deprivation of seeing friends and family die from a disease that seems to be altogether forgotten by Washington bureaucrats. He, too, understands the desire of patients to examine how the organization purporting to represent them is spending its money. He’s squeamish about telling patients not to organize.

In his words: “They SHOULD be angry, and they SHOULD be acting up!”

He hopes the protestors read up a bit more on ACT UP’s story — the parts where they shift their focus away from the FDA toward other targets like the National Institutes of Health. And he maintains there are plenty of potential targets for the ALS patient anger, including insurance companies that deny necessary care, and/or members of Congress who balk at funding basic research.

“I’d do exactly what we did with HIV, I just wouldn’t make the same mistakes we made with 30 years of hindsight,” Gonslaves said. “As we dug deeper, our targets changed. … Hopefully people living with ALS can learn those lessons quickly.”

*From the article here:

 
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mr peabody

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Scientists are using ALS patient cells to re-create blood-brain barrier defects

by Vijaya Iyer | ALS News Today | June 13, 2019

Researchers at Cedars-Sinai Medical Center have re-created the blood-brain barrier, a vital component of the central nervous system, using Organ-Chip technology by Emulate. This advances the possibility of patient-specific treatments for neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS).

Blood-brain barrier defect has been linked to ALS and other neurological conditions.

The laboratory generated blood-brain barriers that not only are structurally similar but also function as they would in individuals whose cells were used to re-create it, the study found.

“The study’s findings open a promising pathway for precision medicine,” Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and a senior author of the study, said in a press release.

The study, “Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications,” was published in the journal Cell Stem Cell.

The function of the blood-brain barrier is to protect the brain from toxins, pathogens, and other foreign substances that may be present in the bloodstream. It also prevents therapeutics from reaching the brain. A faulty blood-brain barrier that also keeps out natural biomolecules required for proper functioning of the brain has been linked to several neurological conditions, including ALS, Huntington’s Disease, and Parkinson’s disease.

Researchers obtained blood samples from volunteers and isolated a particular type of cells called induced pluripotent stem cells (iPSC) from the blood. The iPSCs are stem cells that can develop into any type of cell.

Using iPSCs, the team generated all the components of the barrier (nerve cells, blood vessels, and other support cells). However, for all the components to interact with one another and function as they do in the body, they must be in conditions similar to their natural environment in their original location. For this, the team used organ-chips developed by Emulate. Organ-chips are AA battery-sized transparent units that re-create the body’s microenvironment and flow of blood and air.

Once placed in the organ-chips, the cells formed a tight single layer of the functional unit and worked as a blood-brain barrier just as they would in the body. The barrier also expressed biomarkers (proteins) specific to the brain and prevented the entry of certain therapeutics, the team found.

The researchers also used iPSCs derived from blood samples obtained from patients with Huntington’s disease or another rare brain development disorder called Allan-Herndon-Dudley syndrome in this study. The resulting blood-brain barrier exhibited characteristics specific to the condition, such as the absence of specific protein channels and compromised barrier integrity. It malfunctioned the same way as seen in patients with Huntington’s disease and Allan-Herndon-Dudley syndrome.

“By combining Organ-Chip technology and human iPSC-derived tissue, we have created a neurovascular unit that recapitulates complex [blood-brain barrier] functions, provides a platform for modeling inheritable neurological disorders and advances drug screening, as well as personalized medicine,” the authors wrote.

This study is the result of the collaborative Patient-on-a-Chip program between Cedars-Sinai and Emulate started in February 2018 and initiated by Cedars-Sinai Precision Health. The goal of the program to develop personalized, effective therapies based on the patient’s genetic makeup.

“The possibility of using a patient-specific, multicellular model of a blood-brain barrier on a chip represents a new standard for developing predictive, personalized medicine,” Svendsen said.

 
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What happens in the body of an ALS patient?

Science News | April 15, 2019

Amyotrophic lateral sclerosis (ALS) is an incurable disease of the central nervous system. In most cases, ALS is fatal within a short period following diagnosis. However, people sometimes live with the disease for decades, as did the astrophysicist Stephen Hawking. What happens in the body of an ALS patient? Muscle movement is controlled by specialised neurons called motor neurons. During the course of the disease, motor neurons gradually die. As ALS progresses, patients increasingly suffer from muscle weakness and paralysis, which leads to speech, movement and swallowing disorders, and severe restrictions in daily life.

Which processes lead to neuronal death? This is not yet fully understood, but research has shown that changes in the behavior of certain proteins are directly related to ALS. One of these proteins is the RNA-binding protein FUS (Fused in Sarcoma), which plays a crucial role within cells since it regulates genetic messengers and participates in the interaction of different proteins. Mutations in FUS cause FUS to deposit and aggregate in the cytoplasm, causing one of the most aggressive forms of ALS.

Lara Marrone and Jared Sterneckert from the Centre for Regenerative Therapies Dresden (CRTD) at Technische Universität Dresden (TUD), together with collaborating scientists from Germany, Italy, the Netherlands, and the USA, have now discovered that interactions between RNA-binding proteins are more critical to ALS pathogenesis than previously thought. In their recent paper, the research team showed that impaired FUS protein-protein interactions disrupt the balance (homeostasis) of RNA-binding proteins, which significantly contributes to the degeneration of neurons.

The scientists also showed that drug-induced protein degradation (autophagy) reduces the pathological processes linked to aberrantly accumulated FUS. Stimulating autophagy rescued these RNA-binding proteins and reduced neuronal death. These improvements were observed in cell culture experiments with reprogrammed stem cells (iPS cells) from patients and validated using as the fruit fly as a model organism.

Lara Marrone, PhD student at the CRTD and lead author of the study, explains: "Mislocalised FUS overwhelms the protein degradation machinery, causing FUS to accumulate within the cytoplasm. This triggers a vicious circle that further hampers the cellular protein quality control systems responsible for the maintenance of protein homeostasis. This is why we speculated that enhancing autophagy could also ameliorate the observed RNA-binding phenotypes." The Sterneckert group will now investigate the extent to which enhancing autophagy is a possible therapeutic approach for ALS patients. A further goal of their research is to use RNA-binding proteins in patient samples as biomarkers for the disease.

Jared Sterneckert and his team use induced pluripotent stem cells (iPS cells) to investigate neurodegenerative diseases, such as ALS and Parkinson's disease. They conduct their studies at the CRTD, where top researchers from over 30 countries are deciphering the principles of cell and tissue regeneration for disease diagnosis and treatment. CRTD links laboratory with the clinic, scientists with physicians, and uses expertise in stem cell research, genome editing, and tissue regeneration for curing neurodegenerative diseases such as ALS using novel diagnostic tools and therapies.

 
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Copper compound shows potential as therapy for slowing ALS

Medical Xpress | July 2, 2019

A compound with potential as a treatment for ALS has gained further promise in a new study that showed it improved the condition of mice whose motor neurons had been damaged by an environmental toxin known to cause features of ALS.

ALS patients are categorized either as familial—meaning two or more people in their family have had the disease, which in their case is linked to inherited genetic mutations—or sporadic, which accounts for about 90% of the cases. Sporadic means the cause or causes are unknown.

The research by Joe Beckman at Oregon State University and collaborators at the University of British Columbia builds on a 2016 study by Beckman in which the compound, copper-ATSM, halted familial ALS progression in transgenic mice for nearly two years, allowing them to approach their normal lifespan.

The animals had been genetically engineered to produce a mutation of an antioxidant protein, SOD, that's essential to life when functioning properly but kills motor neurons when it lacks its zinc and copper co-factors and "unfolds." SOD mutations are present in 3% of ALS patients.

ALS, short for amyotrophic lateral sclerosis and also known as Lou Gehrig's disease, is caused by the deterioration and death of motor neurons in the spinal cord. It is progressive, debilitating and fatal.

ALS was first identified in the late 1800s and gained international recognition in 1939 when it was diagnosed in a mysteriously declining Gehrig, ending the Hall of Fame baseball career of the New York Yankees first baseman. Known as the Iron Horse for his durability—he hadn't missed a game in 15 seasons—Gehrig died two years later at age 37.

Scientists have developed an approach to treating ALS that's based on using copper-ATSM to deliver copper to specific cells in the spinal cord. Copper is a metal that helps stabilize the SOD protein and can also help improve mitochondria weakened by the disease.

The entire human body contains only about 100 milligrams of copper, the equivalent of 5 millimeters of household wiring.

"The damage from ALS is happening primarily in the spinal cord, one of the most difficult places in the body to absorb copper," said Beckman, distinguished professor of biochemistry and biophysics in the College of Science and principal investigator and holder of the Burgess and Elizabeth Jamieson Chair at OSU's Linus Pauling Institute. "Copper can be toxic, so its levels are tightly controlled in the body. The therapy we're working toward delivers copper selectively into the cells in the spinal cord that actually need it. Otherwise, the compound keeps copper inert."

In the mid-20th century, it was discovered that indigenous residents of Guam frequently developed an ALS-like disease, known as ALS-Parkinsonism dementia complex (ALS-PDC), and its onset was linked to an environmental toxin produced by cycad trees, whose seeds provided food for animals the sickened people had hunted and ate.

In the new research, Michael Kuo and Chris Shaw at the University of British Columbia along with Beckman used a similar toxin to induce ALS-PDC symptoms in mice, then treated the mice with copper-ATSM.

"With the treatment, the behavior of the sick animals was improved on par with the control animals," Beckman said. "Treatment prevented the extensive motor neuron degeneration seen in the untreated animals. These outcomes support a broader neuroprotective role for copper-ATSM beyond mutant SOD models of ALS with implications for sporadic ALS. It means the copper is doing more than just helping to fix the SOD. One result after another shows the compound is working pretty good."

 
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Boosting gut bacterium may slow the progression of ALS*

by Tina Hesman Saey | Science News | Jul 22 2019

A friendly gut bacterium can help lessen ALS symptoms, a study of mice suggests.

Mice that develop a degenerative nerve disease similar to amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, fared better when bacteria making vitamin B3 were living in their intestines, researchers report July 22 in Nature. Those results suggest that gut microbes may make molecules that can slow progression of the deadly disease.

The researchers uncovered clues that the mouse results may also be important for people with ALS. "But the results are too preliminary to inform any changes in treating the disease, which at any given time affects about two out of every 100,000 people, or about 16,000 people in the United States," says Eran Elinav, a microbiome researcher at the Weizmann Institute of Science in Rehovot, Israel.

“With respect to ALS, the jury is still out,” says Elinav, also of the German Cancer Research Center in Heidelberg. “We have to prove that what we found in mice is reproducibly found in humans.”

Elinav and his colleagues examined the gut microbiomes — bacteria, archaea and other microbes that live in the colon, or large intestine — of mice that produce large amounts of a mutated form of the SOD1 protein. In the mice, as in human ALS patients, faulty SOD1 proteins clump together and lead to the death of nerve cells.

Microbiomes of ALS mice contained almost no Akkermansia muciniphila bacteria. Restoring A. muciniphila in the ALS mice slowed progression of the disease, and the mice lived longer than untreated rodents. By contrast, greater numbers of two other normal gut bacteria, Ruminococcus torques and Parabacteroides distasonis, were associated with more severe symptoms.

Akkernansia has a mixed record when it comes to human health. It’s been linked to protection against type 2 diabetes that comes with aging, and it may help people lose weight and relieve symptoms of inflammatory bowel diseases. "But studies of Alzheimer’s dementia, multiple sclerosis and Parkinson’s disease have associated increased numbers of Akkermansia with worse symptoms," says Brett Finlay, a microbiologist at the University of British Columbia in Vancouver. “So I was surprised to see a beneficial effect of Akkermansia in a brain disease, because, thus far, it’s been associated with poorer outcomes.”

Elinav’s team investigated what Akkermansia does to relieve symptoms that hamper the mice’s ability, for example, to stay on a rotating rod or grip a wire. The researchers focused on molecules, or metabolites, the bacteria produce, including B3.

Giving nicotinamide, a water soluble form of vitamin B3 found in foods and dietary supplements, to ALS mice improved some symptoms. But unlike mice with boosted Akkermansia numbers, the vitamin-supplemented mice didn’t live any longer than untreated mice. "That finding may mean that the bacteria produce other substances or work with other microbes to affect symptoms, which wouldn’t be too surprising," says Jun Sun, a medical microbiologist at the University of Illinois in Chicago. “Usually you don’t expect one miracle metabolite can rescue the mice completely,” she says.

Preliminary work suggests Akkermansia may play a role in human ALS, too. In a small study of 37 ALS patients and 29 healthy family members, Elinav’s group found that people with ALS also have lower levels of Akkermansia in their stool. Levels of nicotinamide in ALS patients’ blood and cerebral spinal fluid were also lower than in healthy people. The lower the levels of nicotinamide in the blood, the more severe the patient’s symptoms, the researchers discovered.

*From the article here:

 
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Bacterium significantly reduces ALS severity in mice*

by Jef Akst | The Scientist | Jul 24 2019

Boosting the levels of the bacterium Akkermansia muciniphila in mice slowed the progression of an ALS-like disease.

In a mouse model of ALS, animals that had ample levels the bacterium Akkermansia muciniphila in their gut microbiomes fared better than those carrying almost no members of the species, which produces vitamin B3, according to a study published this week (July 22) in Nature. Moreover, restoring A. muciniphila in mice that had low levels slowed the progression of their disease.

“When we gave it to ALS-prone mice, it very significantly improved ALS severity in these mice,” co-author Eran Elinav, a microbiome researcher at the Weizmann Institute of Science in Israel and of the German Cancer Research Center in Heidelberg, tells The Guardian. On the other hand, two other members of the microbiome — Ruminococcus torques and Parabacteroides distasonis — were more common in mice with severe disease.

The researchers suspect that A. muciniphila’s production of B3 may have something to do with its apparently therapeutic effects. Treating mice with a form of vitamin B3 called nicotinamide improved some of their symptoms. However, this did not increase the mice’s lifespan as boosting levels of the bacteria had, suggesting there’s more to the bacterium’s effect than just B3. “Usually you don’t expect one miracle metabolite can rescue the mice completely,” Jun Sun, a medical microbiologist at the University of Illinois at Chicago who was not involved in the study, tells Science News.

The researchers gathered some preliminary data that suggest A. muciniphila abundance may relate to ALS in humans as well. Examining the microbiomes of 37 ALS patients and 29 healthy family members, Elinav and colleagues found lower levels of the bacterium in the stool of the ALS patients and lower levels of nicotinamide in their blood and cerebrospinal fluid. In addition, the levels of nicotinamide in the blood correlated with the severity of the patient’s disease: patients with lower levels tended to have worse symptoms.

“We have to prove that what we found in mice is reproducible in humans,” Elinav tells Science News.

*From the article here:

 
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Robotic neck brace dramatically improves function in ALS patients

by Columbia University School of Engineering and Applied Science | Aug 12 2019

A novel neck brace, which supports the neck during its natural motion, was designed by Columbia engineers. This is the first device shown to dramatically assist patients suffering from Amyotrophic Lateral Sclerosis (ALS) in holding their heads and actively supporting them during range of motion. This advance would result in improved quality of life for patients, not only in improving eye contact during conversation, but also in facilitating the use of eyes as a joystick to control movements on a computer, much as scientist Stephen Hawkins famously did.

A team of engineers and neurologists led by Sunil Agrawal, professor of mechanical engineering and of rehabilitation and regenerative medicine, designed a comfortable and wearable robotic neck brace that incorporates both sensors and actuators to adjust the head posture, restoring roughly 70% of the active range of motion of the human head. Using simultaneous measurement of the motion with sensors on the neck brace and surface electromyography (EMG) of the neck muscles, it also becomes a new diagnostic tool for impaired motion of the head-neck. Their pilot study was published August 7 in the Annals of Clinical and Translational Neurology.

The brace also shows promise for clinical use beyond ALS, according to Agrawal, who directs the Robotics and Rehabilitation (ROAR) Laboratory. "The brace would also be useful to modulate rehabilitation for those who have suffered whiplash neck injuries from car accidents or have from poor neck control because of neurological diseases such as cerebral palsy," he said.

"To the best of my knowledge, Professor Agrawal and his team have investigated, for the first time, the muscle mechanisms in the neck muscles of patients with ALS. Their neck brace is such an important step in helping patients with ALS, a devastating and rapidly progressive terminal disease," said Hiroshi Mitsumoto, Wesley J. Howe Professor of neurology at the Eleanor and Lou Gehrig ALS Center at Columbia University Irving Medical Center who, along with Jinsy Andrews, assistant professor of neurology, co-led the study with Agrawal. "We have two medications that have been approved, but they only modestly slow down disease progression. Although we cannot cure the disease at this time, we can improve the patient's quality of life by easing the difficult symptoms with the robotic neck brace."

A Columbia Engineering-designed robotic brace that supports the neck during its natural motion is the first device shown to dramatically assist ALS patients in holding their heads and actively supporting them during range of motion. The comfortable brace incorporates both sensors and actuators to restore roughly 70% of the active range of motion brace and should improve patients' quality of life, not only in improving eye contact during conversation, but also in facilitating the use of eyes as a joystick to control movements on a computer, much as scientist Stephen Hawkins did. Credit: Haohan Zhang and Sunil K. Agrawal/Columbia Engineering

Commonly known as Lou Gehrig's disease, ALS is a neurodegenerative disease characterized by progressive loss of muscle functions, leading to paralysis of the limbs and respiratory failure. Dropped head, due to declining neck muscle strength, is a defining feature of the disease. Over the course of their illness, which can range from several months to more than 10 years, patients completely lose mobility of the head, settling in to a chin-on-chest posture that impairs speech, breathing, and swallowing. Current static neck braces become increasingly uncomfortable and ineffective as the disease progresses.

To test this new robotic device, the team recruited 11 ALS patients along with 10 healthy, age-matched subjects. The participants in the study were asked to perform single-plane motions of the head-neck that included flexion-extension, lateral bending, and axial rotation. The experiments showed that patients with ALS, even in the very early stages of the disease, use a different strategy of head-neck coordination compared to age-matched healthy subjects. These features are well correlated with clinical ALS scores routinely used by clinicians. The measurements collected by the device can be used clinically to better assess head drop and the ALS disease progression.

"In the next phase of our research, we will characterize how active assistance from the neck brace will impact ALS subjects with severe head drop to perform activities of daily life," said Agrawal, who is also a member of Columbia University's Data Science Institute. "For example, they can use their eyes as a joystick to move the head-neck to look at loved ones or objects around them."

 
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Ayahuasca shows potential for treating ALS

by Aaron Kase | Reset.me | 27 May 2015

Is ayahuasca the key to combating destructive neurodegenerative diseases like ALS? That’s the focus of a new article by Daniel Gustafsson, who is studying the connections between ethnobotanical medicine and neurodisease.

While native people in the Amazon have been using ayahuasca for centuries, and its popularity has grown over the last few decades, science has not caught up to the legend. Researchers are trying to remedy the gaps in our knowledge, however. One study currently underway is looking at how ayahuasca can be used to treat people suffering from ALS. According to initial updates, some are experiencing a wider range of movement, tension relief in their muscles and improved grip strength after taking ayahuasca.

There is science behind the hypothesis that ayahusaca could be useful. “Natural substances extracted from the ayahuasca plants have been found to possess unique restorative and strongly antioxidative properties on specific nerve cells in the brain and central nervous system, controlling neurotransmission, muscle/motor activity, memory and coordination," Gustafsson writes.

That means it could be effective against diseases like ALS, which currently has no known cure, as well as Multiple Sclerosis, Alzheimer’s and Parkinson’s. Initial studies have suggested that ayahuasca might actually stimulate new cell growth in areas where these diseases have ravaged the brain.

In addition to the possible physiological benefits for patients with ALS, ayahuasca and other psychedelics can be useful in a psychotherapeutic role as well by helping patients mentally come to grips with their illness.

Other research suggests that ayahuasca could be useful in treating conditions such as spinal chord injuries, diabetes and cancer. Yet scientific studies are still few and far between, because the substance is considered a Schedule I controlled substance with no medical value by the United States government, making it difficult for researchers to get permission to work with it.

There is a ray of hope, however. Banisteriopsis Caapi, one of the plants from which ayahuasca brews are concocted, does not contain any dimethyltryptamine, or DMT. That means that when consumed on its own it doesn’t invoke the psychedelic visions for which ayahuasca is famous, and therefore is not banned in the United States and most other countries. While B. Caapi on its own doesn’t boast the full medicinal portfolio of the true ayahuasca drink, it might still be helpful for people facing ALS and other diseases who can’t find relief anywhere else.

"One big step," Gustafsson argues, "would be to stop calling plant-based psychedelics 'drugs,' and lumping them in with more harmful substances that are tied to public health problems. A more correct term for these plants, with respect to the indigenous culture in which ayahuasca is a part of, would be ‘entheogens',” he writes, “which means plants used in a context sacred to the native people, inducing spiritual experiences.”

http://reset.me/story/ayahuasca-show...-to-treat-als/
 
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New insight into motor neuron death mechanisms could be a step toward ALS treatment

by Steve Lundeberg | Medical Xpress | Sep 4 2019

Researchers at Oregon State University have made an important advance toward understanding why certain cells in the nervous system are prone to breaking down and dying, which is what happens in patients with ALS and other neurodegenerative disorders.

The study into the role a protein known as heat shock protein 90 plays in intracellular signaling is a key step on the way to figuring out the reason some motor neurons in the spinal cord die and some do not.

Findings, which could eventually lead to therapies to counter motor neuron death, were published in Experimental Biology and Medicine.

Neurons are cells in the nervous system that carry information to muscles, glands and other nerves. Motor neurons are large neurons in the spine and brain stem, with long axons extending outside the nervous system to contact muscles and control their movements via contraction.

Researchers led by Alvaro Estevez and Maria Clara Franco of the OSU College of Science have shown that a ubiquitous "protein chaperone," heat shock protein 90, is particularly sensitive to inhibition in motor neurons that depend for survival on "trophic factors"—small proteins that serve as helper molecules.

Trophic factors attach to docking sites on the surface of nerve cells, setting in motion processes that help keep a cell alive. Research in animal models has shown trophic factors may have the ability to salvage dying neurons.

"It is well known that there are some motor neuron subpopulations resistant to degeneration in ALS, and other subpopulations that are highly susceptible to degeneration," said Estevez, associate professor of biochemistry and biophysics and the corresponding author on this research. "Understanding the mechanisms involved in these different predispositions could provide new insight into how ALS progresses and open new alternatives for the development of novel treatments for the disease."

In this study, a motor-neuron-specific pool of heat shock protein 90, also known as Hsp90, repressed activation of a key cellular receptor and thus was shown to be critical to neuron survival; when Hsp90 was inhibited, motor neuron death was triggered.

The Hsp90 inhibitor used in this research was geldanamycin, an antitumor antibiotic used in chemotherapy. Findings suggest the drug may have the unintended consequence of decreasing motor neurons' trophic pathways and thus putting those nerve cells at risk.

"The inhibition of Hsp90 as a therapeutic approach may require the development of inhibitors that are more selective so the cancer cells are targeted and healthy motor neurons are not," said Franco, assistant professor of biochemistry and biophysics.

ALS. also known as Lou Gehrig's disease, is caused by the deterioration and death of motor neurons in the spinal cord. It is progressive, debilitating and fatal.

 
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Toxin produced by cyanobacteria, a blue-green algae in marine ecosystems.

Contact with marine algae toxin may lead to ALS*

Neuroscience News | Sep 17 2019

Researchers are investigating an environmental toxin called BMAA that has been linked to significantly increased occurrence of sporadic ALS in populations with frequent dietary consumption of food sources containing high levels of BMAA — including the Chamorro population of Guam where ALS incidence is approximately 100 times greater than other populations.

The toxin is produced by cyanobacteria, a blue-green algae, and can occur in marine ecosystems. According to the researchers, BMAA accumulates in sharks, shellfish and bottom feeders — so populations relying mainly on these food sources may be at risk.

Elizabeth Proctor, assistant professor of neurosurgery, and Nikolay Dokholyan, professor of pharmacology, used a computer to investigate why exposure to the toxin may lead to the development of diseases like ALS.

According to the researchers, if BMAA becomes part of a protein called copper-zinc superoxide dismutase (SOD1), the protein may adopt a form that is toxic to neurons.

Proctor, who holds a doctorate in bioinformatics and computational biology, said the study may be a model for investigating non-genetic cases of ALS, which account for 90% of all diagnoses.

“Our results suggest a need for further investigation of SOD1 modification patterns in ALS patients,” Proctor said. “If we can determine the molecular patterns of disease onset and progression, it may aid in the development of lifestyle and preventative interventions for sporadic ALS.”

What eluded researchers was an explanation for why BMAA led to the development of ALS and other neurodegenerative diseases.

In their study, published in PLOS Computational Biology, Proctor and Dokholyan proposed that BMAA causes the protein SOD1 to fold into a form that is toxic to neurons.

Proteins are built using 20 amino acids according to specific “recipes” coded in DNA. Slight changes to the “ingredients” can result in proteins that aren’t able to function the way they are supposed to. Proctor said if enough BMAA is present in a motor neuron that is building SOD1, it may be mistaken for the amino acid L-serine, which has similar properties.

According to the researchers, who used computer modeling to see what the protein would look like with BMAA instead of serine, this substitution critically alters the structure and stability of the protein.

More than 150 mutations of SOD1 have been associated with ALS, but the structural changes from those mutations aren’t enough to affect the stability of the protein according to Nikolay Dokholyan, professor of pharmacology and co-author of the study.

“SOD1 has a higher level of stability compared to most normal proteins,” said Dokholyan, who has a doctorate in physics. “Although many mutations in this protein are associated with ALS, the resulting changes to its structure are not strong enough to cause significant destabilization.”

Serine, the amino acid that BMAA competes with, occurs ten times in the “recipe” for SOD1. The researchers tested their theory by substituting BMAA for serine in each of those ten occurrences using a computer program developed by Dokholyan. They observed that BMAA incorporation had detrimental effects to the structure and stability of the protein and caused it to fold, or adopt its shape, incorrectly.

According to the researchers, studying patterns of SOD1 modifications in patients may be useful in developing potential interventions for sporadic ALS. One example of a possible intervention is L-serine supplementation for people exposed to a high amount of BMAA.

Although the study suggestions a connection between two pieces of ALS evidence, Dokholyan says many molecular factors contribute to the presentation of symptoms that doctors see.

“A variety of gene mutations and external factors, like BMAA exposure, are associated with ALS,” Dokholyan said. “If we can figure out one pattern, it may give clues for how to unlock others.”

*From the article here :
 
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Injection of virus-delivered gene silencer blocks ALS degeneration*

University of California, San Diego | Medical Xpress | Dec 23 2019

An international team headed by researchers at University of California San Diego School of Medicine describe a new way to effectively deliver a gene-silencing vector to adult amyotrophic lateral sclerosis (ALS) mice, resulting in long-term suppression of the degenerative motor neuron disorder if treatment vector is delivered prior to disease onset, and blockage of disease progression in adult animals if treatment is initiated when symptoms have already appeared.

The findings are published in the December 23, 2019 online issue of the journal Nature Medicine. Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine and a member of the Sanford Consortium for Regenerative Medicine, is senior author of the study.

ALS is a neurodegenerative disease that affects nerve cells in the brain and spinal cord. Motor neurons responsible for communicating movement are specifically harmed, with subsequent, progressive loss of muscle control affecting the ability to speak, eat, move and breathe. More than 5,000 Americans are diagnosed with ALS each year, with an estimated 30,000 persons currently living with the disease. While there are symptomatic treatments for ALS, there is currently no cure. The majority of patients succumb to the disease two to five years after diagnosis.

There are two types of ALS, sporadic and familial. Sporadic is the most common form, accounting for 90 to 95 percent of all cases. It may affect anyone. Familial ALS accounts for 5 to 10 percent of all cases in the United States, and is inherited. Previous studies show that at least 200 mutations of a gene called SOD1 are linked to ALS.

The SOD1 gene normally serves to provide instructions for making an enzyme called superoxide dismutase, which is widely used to break down superoxide radicals—toxic oxygen molecules produced as a byproduct of normal cell processes. Previous research has suggested that SOD1 gene mutations may result in ineffective removal of superoxide radicals or create other toxicities that cause motor neuron cell death, resulting in ALS.

The new approach involves injecting shRNA—an artificial RNA molecule capable of silencing or turning off a targeted gene—that is delivered to cells via a harmless adeno-associated virus. In the new research, single injections of the shRNA-carrying virus were placed at two sites in the spinal cord of adult mice expressing an ALS-causing mutation of the SOD1 gene, either just before disease onset or when the animals had begun showing symptoms.

Earlier efforts elsewhere had involved introducing the silencing vector intravenously or into cerebrospinal fluid in early symptomatic mice, but disease progression, while delayed, continued and the mice soon died. In the new study, the single subpial injection (delivered below the pia matter, the delicate innermost membrane enveloping the brain and spinal cord) markedly mitigated neurodegeneration in pre-symptomatic mice, which displayed normal neurological function with no detectable disease onset. The functional effect corresponded with near-complete protection of motor neurons and other cells, including the junctions between neurons and muscle fibers.

In adult mice already displaying ALS-like symptoms, the injection effectively blocked further disease progression and degeneration of motor neurons.

In both approaches, the affected mice lived without negative side effects for the length of the study.

"At present, this therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS," said senior author Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine.

"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."

The research team also tested the injection approach in adult pigs, whose spinal cord dimensions are similar to humans, for safety and efficacy. Using an injection device developed for use in adult humans, they found the procedure could be performed reliably and without surgical complications.

Marsala said next steps involve additional safety studies with a large animal model to determine the optimal, safe dosage of treatment vector. "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 species more similar to humans is a critical step in advancing this treatment approach toward clinical testing."

*From the article here :
 
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Quercetin in the treatment of neurological disorders

Amanzadeh, Esmaeili, Rahgozar, Nourbakhshnia

Quercetin is a polyphenolic flavonoid, which is frequently found in fruits and vegetables. The antioxidant potential of quercetin has been studied from subcellular compartments, that is, mitochondria to tissue levels in the brain. The neurodegeneration process initiates alongside aging of the neurons. It appears in different parts of the brain as Aβ plaques, neurofibrillary tangles, Lewy bodies, Pick bodies, and others, which leads to Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and other diseases. So far, no specific treatment has been identified for these diseases. Despite common treatments that help to prevent the development of disease, the condition of patients with progressive neurodegenerative diseases usually do not completely improve. Currently, the use of flavonoids, especially quercetin for the treatment of neurodegenerative diseases, has been expanded in animal models. It has also been used to treat animal models of neurodegenerative diseases. In addition, improvements in behavioral levels, as well as in cellular and molecular levels, decreased activity of antioxidant and apoptotic proteins, and increased levels of antiapoptotic proteins have been observed. Low bioavailability of quercetin has also led researchers to construct various quercetin-involved nanoparticles. The treatment of animal models of neurodegeneration using quercetin-involved nanoparticles has shown that improvements are observed in shorter periods and with use of lower concentrations. Indeed, intranasal administration of quercetin-involved nanoparticles, constructing superparamagnetic nanoparticles, and combinational treatment using nanoparticles such as quercetin and other drugs are suggested for future studies.

 
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How one man is speaking up for ALS patients, even without his voice

CBC Radio | Oct 25 2019

"People living with ALS are 'very frustrated' with elements of health-care system," advocate says.

Jay DesMazes is "100 per cent dependent" on his tablet to communicate.

Bedridden with extremely limited movement, the 56-year-old is living with the latter stages of amyotrophic lateral sclerosis (ALS), a genetic disease. A ventilator pumps air into his lungs via a tracheostomy.

He lost the ability to speak over a year ago. Now, as DesMazes lies in a hospital bed, his eyes dart around at an iPad. A camera perched atop the tablet picks up the eye movement, matching it to a letter on the screen.

DesMazes assembles words one letter at a time. A synthesizer reads the sentences he writes.

"Without it, I would be insane," DesMazes said of the tablet.

So much so that he describes three days without the device in a Surrey, B.C., hospital as equivalent to "having your mouth taped shut."

"That is what it's like when you can't communicate at all."


No tablet for 3 days

White Coat, Black Art's Dr. Brian Goldman recently visited DesMazes in the High Acuity Unit of the Abbotsford Regional Hospital, where he has been for the past two months. He provided DesMazes with a list of questions ahead of his visit. DesMazes spent hours typing out his answers, describing his life with ALS and alleging mistreatment during his care at Surrey Memorial Hospital.

Earlier this year, DesMazes was taken to the hospital in respiratory distress. He says he had just been transferred to the hospital and claims staff didn't read the instructions that accompanied him.

"I have a specific set of instructions that moves with me everywhere I go. The nurse didn't take the time to read instructions," DesMazes said. "She couldn't get me lined up properly to use the computer. She assumed the computer was broken and she took it away from me."

DesMazes is completely dependent on his care providers for everything from keeping his airway clear, feeding and toileting him, moving him so he doesn't get bedsores, and positioning his head so he can use his speech device.

According to DesMazes's account, he was without the tablet for three days, until his brother and advocate, Michael DesMazes visited.

"I have a specific set of instructions that moves with me everywhere I go. The nurse didn't take the time to read instructions," DesMazes said. "She couldn't get me lined up properly to use the computer. She assumed the computer was broken and she took it away from me."

DesMazes is completely dependent on his care providers for everything from keeping his airway clear, feeding and toileting him, moving him so he doesn't get bedsores, and positioning his head so he can use his speech device.

According to DesMazes's account, he was without the tablet for three days, until his brother and advocate, Michael DesMazes visited.

"This meant I couldn't tell them when I had a bowel movement or when I was uncomfortable."

Michael DesMazes says there have been repeated problems with staff not "taking the time to listen to his needs, or to listen to his aches and pains."

Tammy Moore, CEO of ALS Society of Canada, says there are about 3,000 people living with ALS in Canada. She's heard similar accounts from other ALS patients about a communication device being inaccessible, and the consequences can be severe.

"If you're in a hospital and that equipment isn't set up, you can't communicate. As one client said, 'If I'm sitting beside you, I could be choking to death and you wouldn't know it.'"

The brothers say they complained about the care at Surrey Memorial Hospital. However, a spokesperson with Fraser Health Authority, which oversees the hospital, said it did not receive a complaint to its Patient Care Quality Office, but encouraged the family to follow up on their concerns.

"We always strive to provide quality, timely care to all of our patients...and encourage them to speak directly with their care teams in order to address their concerns in the moment," the statement continued.

'Appropriate' home care, palliative support needed

Moore says people living with ALS are "very frustrated with access to many elements of the health-care system."

"If Canadians understood what the personal experience is of people with ALS, they would be horrified."

"At some point, every person with ALS will have an issue with the health-care system. It would be surprising if they didn't."


Jay DesMazes recalls his stay at an Abbotsford, B.C., care home, in which he says he was "forced to hold urine and bowel movements for hours on end. I've been ignored for hours on end, like, I've screamed and cried for 10 to 12 hours at a time."

He says more care aides are needed.

"They're grotesquely overworked at all levels. There needs to be more education. There's not enough people with this disease to make the governments sit up and listen, sadly."

Moore says "more attention needs to be paid to these vulnerable patients. ALS Canada, and its partner societies, have just finished creating detailed clinical guidelines for treating people with ALS that will be published next year."

"Oftentimes, the support workers are completely untrained in ALS. We need to have appropriate home care and palliative support. This is critical for people who have ALS,"
she said.

 
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CBD may prolong life for those suffering with ALS

by Lisa Rough | Leafly | 19 June 2015

Based on some exciting new anecdotal evidence, the use of cannabis oil to treat ALS may actually prolong life in addition to relieving many of the diseases devastating day-to-day symptoms.

ALS or Lou Gehrig's disease, named after the baseball legend, is a debilitating disorder that affects an estimated 30,000 people in the United States at any given time. You might remember ALS from that craze last summer when everyone decided to dump ice on their heads to raise awareness for the disease and to raise money for ALS research. Even Leafly hopped on the bandwagon for a good cause, and overall, the ALS Foundation received over $100 million in donations by the time the summer of the Ice Bucket Challenge was over.

ALS is a degenerative neurological disorder that causes muscle weakness, wasting, and paralysis of the limbs, as well as those that control vital functions such as speech, swallowing, and breathing. It is often the deterioration of these crucial muscles that leads to respiratory failure; even with breathing aids or a tracheotomy, the risk of respiratory failure persists.

Being diagnosed with ALS is devastating, and for many it can feel like a death sentence. The average life expectancy of a person with ALS is two to five years. However, more than half of all people with ALS live more than three years from diagnosis and there are definitely outliers, such as Stephen Hawking, one of the most iconic figures with ALS. Hawking was diagnosed in 1963, and now, more than 30 years later, he is among only 5% of those diagnosed with ALS who live more than 20 years after diagnosis.

Cannabis has long been known as a viable treatment option to relieve symptoms of ALS, which was outlined in this handy chart created by the American Journal of Hospice and Palliative Medicine, but the most astonishing results have come from several ALS sufferers who have managed to slow the progression of the disease through regular, controlled doses of cannabis oil.

Bob Strider began experiencing the symptoms of ALS in 1998, specifically the loss of function in his right arm and problems swallowing. An avid cannabis enthusiast, he had used cannabis heavily for decades, which he believes has kept the progression of his disease slow but steady. In 2012, Strider began manufacturing his own cannabis oils, dosing himself with approximately a gram a day for 60 days. Within 10 days of his regimen, he regained control of his right arm and was able to stop using opiates to manage his pain.

Another remarkable case comes from Cathy Jordan, who was diagnosed with ALS in 1986 and given less than five years to live. In the winter of 1989, Jordan spent the holiday in Florida, preparing for the end of her life, when she made a crucial discovery. While walking on the beach one night, she smoked a joint of Myakka Gold and felt her symptoms cease, essentially experiencing the neuroprotective effects of cannabis before they'd been proven.

Jordan never set out to be a cannabis activist, preferring instead to quietly continue treating her disease. She tried to tell her neurologist in 1989 that cannabis had helped her, and he tried to convince her husband to have her committed to a mental facility. In 1994, Jordan met a new doctor who was astonished by her progress. When he asked what shed been doing to stay alive, she informed him, and he advised her, Smoke all the cannabis you can and never tell a soul, because they will never believe you.

Unfortunately, Donnie Clark, the grower of Myakka Gold, was arrested and sent to prison for 12 years until his sentence was commuted by former President Clinton. The strain itself, which Jordan credits with stopping the progression of her ALS, has since been eradicated by the DEA.

Cathy Jordan, however, ended up becoming the inspiration for Amendment 2, the medical marijuana initiative in Florida that was edged out last November. Ironically, on February 25, 2013, the same day that the Cathy Jordan Medical Cannabis Amendment was announced, Jordan's home was raided and 23 plants were seized by local authorities, although charges were dropped when it became evident that she was using cannabis for medicinal purposes.

Now, finally, years later, there has been more and more conclusive research indicating that these patients self-medicating regimen was beneficial, after all. Pre-clinical data shows that cannabis has powerful anti-oxidative, anti-inflammatory, and neuroprotective effects, and with regular applications, it may actually slow the progress of the disease and prolong the lives of the individuals affected by ALS.

Amyotrophic Lateral Sclerosis is a qualifying condition for medical marijuana programs in Delaware, Washington, D.C., Georgia, Illinois, Maine, Massachusetts, Michigan, New Jersey, New Mexico, and New York. However, with more promising research emerging, other states medical marijuana programs need to follow suit and allow suffering patients the Right to Try and treat this horrible disease with cannabis if it can provide them with even a little bit of relief.

https://www.leafly.com/news/science-...gression-of-al
 
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mr peabody

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New clues about the origins of familial forms of ALS

by INBEB | Medical Xpress | Dec 2 2019

A team led by Brazilian researcher Elis Eleutherio, professor at the Federal University of Rio de Janeiro, in partnership with Tiago Outeiro, at University of Goettingen, Germany, made important progress in understanding the conformation and accumulation of certain proteins involved in ALS.

"We believe protein accumulation is an important hallmark of ALS, and we still do not understand why the protein misbehaves and aggregates during the disease," explains Prof. Eleutherio.

ALS is a progressive and devastating neurodegenerative disorder affecting 1 to 3 individuals in 100,000, and it is more prevalent in people between 55-75 years of age. The disease affects primarily a population of neurons known as 'motor neurons.' Patients suffer from irreversible motor paralysis, and become incapable of speaking, swallowing, or breathing as the disease progresses.

Most ALS cases are sporadic, with no defined genetic origin, and only the minority is familial, with known associated genetic alterations. Certain familial forms of ALS (fALS) are associated with genetic alterations in the gene encoding for a protein known as superoxide dismutase 1 (Sod1), that cause alterations in the folding and function of the protein.

The study, published in the journal Proceedings of the National Academy of Sciences (PNAS), allowed scientists to understand the interaction between the normal and the mutant protein, which causes alteration of protein accumulation in the cell, but also impairs the function of the Sod1 protein, thus contributing to the development of the disease. For the group, this discovery opens new perspectives for the treatment of ALS.

Sod1 is a protein that plays a role, among others, in the protection against oxidative damage in our cells. In some ALS cases, altered Sod1 protein accumulates inside neuronal cells and, researchers believe, causes damage to the neurons, leading to their death. Importantly, normal Sod1 proteins present in sporadic cases of ALS, can also misfold and accumulate, suggesting this is a central problem in ALS.

In the study, the researchers used simple experimental models, such as bakery yeast used to make beer, wine and bread, and human cells, in order to better understand the context of protein aggregation in the disease. They also used a strategy that mimics the genetic context of fALS, where most patients carry one copy of the normal Sod1 protein, and one copy carrying a genetic alteration. "In patients, we think that the presence of a mutant copy of Sod1 alters the behavior of the normal copy," explains Dr. Aline Brasil, first author of the study.

"By taking advantage of novel genetic manipulation tools, and powerful molecular imaging approaches that enable the direct visualization of protein complexes in the cell (a technique known as BiFC), we were able to detect 'hetero-complexes' formed by normal and abnormal (mutant) Sod1 protein," said Prof. Outeiro, leader of the German team that participated in the study.

The research opens novel perspectives for therapeutic intervention that the authors hope to continue to explore in the near future, such as the specific removal of mutant Sod1 protein.

"In a time when the scientific and educational system in Brazil suffers from uncertainty, it is important to demonstrate that we can be competitive and conduct research that will contribute to society and may, ultimately, help change the lives of those affected by such devastating diseases," Prof. Eleutherio concludes.

 
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UC San Diego School of Medicine

Injection of virus-delivered gene silencer blocks ALS degeneration

UC San Diego | Medical Xpress | Dec 30 2019

An international team headed by researchers at UC San Diego School of Medicine describe a new way to effectively deliver a gene-silencing vector to adult ALS mice, resulting in long-term suppression of the degenerative motor neuron disorder if treatment vector is delivered prior to disease onset, and blockage of disease progression in adult animals if treatment is initiated when symptoms have already appeared.

The findings are published in the December 23, 2019 online issue of the journal Nature Medicine. Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine and a member of the Sanford Consortium for Regenerative Medicine, is senior author of the study.

ALS is a neurodegenerative disease that affects nerve cells in the brain and spinal cord. Motor neurons responsible for communicating movement are specifically harmed, with subsequent, progressive loss of muscle control affecting the ability to speak, eat, move and breathe. More than 5,000 Americans are diagnosed with ALS each year, with an estimated 30,000 persons currently living with the disease. While there are symptomatic treatments for ALS, there is currently no cure. The majority of patients succumb to the disease two to five years after diagnosis.

There are two types of ALS, sporadic and familial. Sporadic is the most common form, accounting for 90 to 95 percent of all cases. It may affect anyone. Familial ALS accounts for 5 to 10 percent of all cases in the United States, and is inherited. Previous studies show that at least 200 mutations of a gene called SOD1 are linked to ALS.

The SOD1 gene normally serves to provide instructions for making an enzyme called superoxide dismutase, which is widely used to break down superoxide radicals—toxic oxygen molecules produced as a byproduct of normal cell processes. Previous research has suggested that SOD1 gene mutations may result in ineffective removal of superoxide radicals or create other toxicities that cause motor neuron cell death, resulting in ALS.


Blocking ALS motor neuron degeneration by injecting a virus-delivered gene silencer

The new approach involves injecting shRNA—an artificial RNA molecule capable of silencing or turning off a targeted gene—that is delivered to cells via a harmless adeno-associated virus. In the new research, single injections of the shRNA-carrying virus were placed at two sites in the spinal cord of adult mice expressing an ALS-causing mutation of the SOD1 gene, either just before disease onset or when the animals had begun showing symptoms.

Earlier efforts elsewhere had involved introducing the silencing vector intravenously or into cerebrospinal fluid in early symptomatic mice, but disease progression, while delayed, continued and the mice soon died. In the new study, the single subpial injection (delivered below the pia matter, the delicate innermost membrane enveloping the brain and spinal cord) markedly mitigated neurodegeneration in pre-symptomatic mice, which displayed normal neurological function with no detectable disease onset. The functional effect corresponded with near-complete protection of motor neurons and other cells, including the junctions between neurons and muscle fibers.

In adult mice already displaying ALS-like symptoms, the injection effectively blocked further disease progression and degeneration of motor neurons.

In both approaches, the affected mice lived without negative side effects for the length of the study.

"At present, this therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS," said senior author Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine.

"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."

The research team also tested the injection approach in adult pigs, whose spinal cord dimensions are similar to humans, for safety and efficacy. Using an injection device developed for use in adult humans, they found the procedure could be performed reliably and without surgical complications.

Marsala said next steps involve additional safety studies with a large animal model to determine the optimal, safe dosage of treatment vector. "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 species more similar to humans is a critical step in advancing this treatment approach toward clinical testing."

 
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