• Psychedelic Medicine

ALS | +50 articles

mr peabody

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Prof. Stephen Hawking

Ayahuasca and ALS

Male, 65, UK, diagnosed with ALS (not Prof. Hawking)

What can you tell us in general about your medical condition, and to what degree has it affected you? (Prior to treatment using ayahuasca)

My prognosis as of March 2013 was that of a one-year life expectancy, I did get a specific MND diagnosis confirmed by a consultant neurologist, on the back of which an insurance company paid up on my critical illness cover, there being a clear understanding that I would probably not last the year. I was very weak and trembly, had lost over 20 pounds in muscle mass, my knees were prone to swelling and I was racked by cramps and muscle twitching. I could barely manage stairs, and couldn't get out of the bath unassisted. I remember being a little challenged by a four inch step across the end of the room, choosing my best leg to step down.

Describe a typical experience with ayahuasca. What is it like during the immediate time the medicine is active in the body? What has been experienced afterwards?

Initially a fair amount of retching, although I didn't actually vomit much. Then some spastic activity, after which a warmth spread throughout my chest cavity, and sensations from the connection between muscle tissue and skeletal bone. It left me exhausted, but it mellowed out? after a while into a contemplation state of mind where the concept of fear had a major part. Stressful emotions such as fear and anxiety seems to be a major vexation (in relation to neurological diseases), and the ayahuasca seemed to soothe that too. I didn't feel that much different immediately afterwards, I suppose I felt a little more relaxed, but the following weeks (after sessions) my massage therapist said the muscle twitching was much improved, and I continued to recover steadily.

Has this treatment relieved or improved your condition in any way so far?

I have made essentially a full recovery, slow but persistent, and NHS consultants involved are mystified. Ayahuasca seems to me to have been instrumental in my recovery, which is fully documented. I am now fully healthy, I cycle to work. Now, after today doing a nine mile coastal walk for the pleasure it, I feel pretty much up to snuff, for a man of my age. A year after my diagnosis I held a party to express my gratitude to all the people who had helped me through, including T.H., the consultant neurologist (he didn't actually come). I was by that time much better, not up to full strength, but could party on and play the saxophone. I told my doctors about ayahuasca in August of 2013 I think, it was for a six monthly reassessment of my condition. T.H was frankly astonished, and when challenged said that the diagnosis was absolutely sound adding that the nerve conductivity tests were particularly unequivocal. It was then that I told him about the ayahuasca, and rather sheepishly, and mistakenly, he asked me if I had had a good trip? I replied that it had been unpleasant and that it was not a therapy for the faint-hearted. Since then T.H. has presented my case to some regional peer group, and a professor K.T. Their response was that perhaps 'I had a mimi', which seems to be exactly the same as the disease except for the outcome; or that the condition 'might have been brought upon me by the cocktail of therapies' I was taking at the time. I have yet to make a measured response to this, but it was not until I had serious symptoms that were initially interpreted as Lyme disease or an atypical sero-negative rheumatoid arthritic condition, that I embarked on any kind of medical therapy at all. The history presents a persuasive argument. My family, friends and some of my patients are aware of my ayahuasca treatment and are generally supportive. My wife plays tennis with a number of retired GPs, and their general opinion is that whatever I did cant be too bad. Hell, I am still walking about and they were initially supporting my wife and family on the clear expectation of my imminent demise.

Will you continue this treatment? If so, will you make any changes to your current regimen?

I don't see any necessity to carry on being treated. I might do the ayahuasca again but that would really be just out of curiosity.

Have you been following any particular diet prior to, or during your treatment?

Lots of organic fruit and vegetables, and I have a small holding so we have organic lamb and chicken too. I haven't eaten dairy for the past two years, and I seldom drink alcohol though I had a glass of cider the other day.

What made you try this alternative treatment?

It was an inspired patient who in doing an art degree in Plymouth came across the (ayahuasca) visionary art, and drew my attention to its source. Curiously some members of the church group with whom I sit proved an unexpected source of interest and loaned me various books on the topic, including those of the late Alexander Shulgin.

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Amyotrophic Lateral Sclerosis, or Lou Gehrig’s Disease, is a progressive, degenerative neuromuscular disease that affects the nerve cells in the brain and spinal cord. These motor neurons carry messages from the brain to the spinal cord and, ultimately, to the muscles that are necessary for voluntary and involuntary movement and function.

In people living with ALS, motor neurons progressively die and the brain can no longer communicate with the muscles through the spinal cord. As muscles are used less and less frequently, they can atrophy, causing people with ALS to lose the ability to perform everyday activities, such as walking, speaking, and eating. ALS also affects the diaphragm, an essential muscle responsible for breathing, so people with ALS eventually lose their ability to breathe on their own. The average life expectancy for ALS patients is three to five years after diagnosis and death is generally caused by respiratory failure. There is no known cause or cure for ALS.

Cytokinetics is driven to improve the lives of people fighting ALS by applying our understanding of the mechanics of muscle function and contractility to the discovery and development of novel potential treatments that may directly improve muscle function, potentially delaying disease progression and preserving independence.

 
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Ibogaine and neurodegenerative disorders

This is a summary on existing research looking at the influence of Ibogaine on glial cell line-derived neurotrophic factor (GDNF) levels in the brain, and the beneficial impact that an increase in this protein can have. While existing studies have examined these areas, few have identified a possible link between Ibogaine, GDNF expression and neurodegenerative diseases.

Parkinson's Disease and ALS are chronic disorders with no known cure, and require management with drugs that can have considerable side effects, causing a very poor quality of life for terminal stage sufferers of these diseases. By contrast, a low dose regime of Ibogaine or Iboga alkaloid extract would be of low toxicity and free of serious side effects.

GDNF has been shown to have potent neurotrophic factor in both rodent and primate models of Parkinson's. Direct brain infusion of GDNF into the brains of five Parkinson sufferers resulted in a 39% improvement in the off-medication motor sub-score of the Unite Parkinsons Disease Rating Scale, and a 61% improvement in the activities of daily living sub score.

Positron emission tomography (PET) scans of dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, indicating a direct effect of GDNF on dopamine function. Furthermore, after one year, no serious clinical side effects were observed. The use of Iboga alkaloid extract or Ibogaine would provide a longer term and much less invasive method of GDNF administration than direct brain infusion. Thus, further research on Ibogaine and GDNF is certainly warranted.

Regarding motor neuron disease, the little research that has occurred in this area, such as gene transfer of neurotrophic factors, suggests potential in the treatment of motor neuron disease. Again, Ibogaine therapy may offer a straightforward, non-invasive, cheap, low-toxicity method of treatment for sufferers of this disease.

@Bancopuma
 
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Dr. Tom Grodski

Low dose ibogaine

by Dr. Tom Grodski

Parkinson’s disease, ALS and Alzheimer’s are chronic disorders with no known cure. Most neurodegenerative diseases require management with prescription medications that can have considerable side effects, which may cause a very poor quality of life for terminal sufferers. In turn, Ibogaine may be very beneficial to those with degenerative neurological diseases.

Ibogaine is a naturally occurring psychoactive indole alkaloid derived from the roots of the African rain forest shrub Tabernanthe iboga. Ibogaine is part of the Apocynaceae family and traditionally used by the Bwiti, indigenous peoples of Western Africa; in low doses to combat fatigue, hunger and thirst.

Ibogaine increases levels of glial cell line-derived neurotrophic factor (GDNF) in the brain, and this appears to have neuroprotective properties that promote the survival of both dopaminergic and motor neurons. GDNF can also cause sprouting of dopaminergic fibers and clinical improvement in experimental animal and human studies in which the test subjects had Parkinson’s Disease, with the resultant clinical improvement in symptoms. GDNF has been shown to have potent neurotrophic factor in both rodent and primate models of Parkinson’s disease.

Direct brain infusion of GDNF into the brains of five Parkinson sufferers resulted in a 39% improvement in the off-medication motor sub-score of the Unite Parkinson’s Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub score. Positron emission tomography (PET) scans of dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, indicating a direct effect of GDNF on dopamine function. Further, after one year, no serious clinical side effects were observed.

The use of Iboga alkaloid extract or Ibogaine would provide a longer term and much less invasive method of GDNF administration than direct brain infusion. Thus, further research on Ibogaine and GDNF is certainly warranted. Ibogaine therapy may offer a non-invasive and low-toxicity method of treatment for sufferers of these disorders.​
 
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'Patients say ayahuasca is like a reboot for the brain'

by Ayelett Shani Aug 30, 2018

The reason psychoactive drugs are banned is strictly cultural, says neurobiologist Dr. Ido Magen from the Weizmann Institute of Science. We need to free ourselves from the dichotomy between drugs and medications

What is it with you and drugs?

I did my doctorate under Prof. Raphael Meshulam on the subject of cannabis. The truth is that it’s not something that I was aiming for. It turned out that I got to a lab that happened to be doing a study with Meshulam, who is the high priest of cannabis worldwide. The idea was to use substances that he synthesizes from cannabis to treat a liver disease. We used CBD, which is the non-psychoactive element in cannabis, and saw that it actually worked.

Back when I was working on my Ph.D., I asked myself how it was possible that alcohol is legal and cannabis isn’t. That really bugged me. I knew from the research that it’s not a dangerous substance. As I extended my knowledge on the subject, I saw that the source of the ban on cannabis is actually cultural: racism toward Hispanics who immigrated to the United States in the 1930s. My interest only deepened. I began to collect material systematically, and at some point I started to lecture on drugs and to write articles. Somehow it gathered momentum.

Today, in my day-to-day work I am investigating the disease ALS [Lou Gehrig’s Disease] from completely different directions, but I continue to take an interest in psychoactive drugs and to lecture and write on the subject.

You are also active publicly on the subject. I saw an extremely sharp letter that you sent to the Israel Anti-Drug Authority.

As someone who deals with the subject from the scientific angle, I consider it absolutely a mission to illuminate the issue from that perspective and perhaps also to uproot the ignorance that characterizes the authorities’ entire attitude toward drugs. I really don’t like the messages that the IADA transmits to the broad public. I don’t like the fact that the state authorities are lying, simply disseminating fake news – or presenting alternative facts, to put it more mildly.

You are critical of the “gateway theory” – cannabis serving as the entryway to hard drugs, the joint that morphs into a syringe, etc.

The IADA claims that there is scientific proof that cannabis leads to the use of hard drugs down the line. That is a total lie. Even the authority itself makes opposite claims on its web page. It presents many figures as being factual, even though they have no empirical basis. For example, that a chronic use of cannabis leads to addiction and that the attempt to stop smoking it involves rehab with harsh physical symptoms; or data about the physical damage that smoking weed entails, among them a heightened risk of fatal diseases, damage to the respiratory system and so forth – whereas there are conflicting and not unequivocal findings about all those effects.

I think that the messages should be accurate and based on facts. In this era, in which people are exposed to a great deal of information, it’s anachronistic, not to say ridiculous, to continue to disseminate messages that are clearly far from the truth.

Many influential people are meddling in the legalization issue.

I think that certain enforcement agencies have an interest in continuing this line, because it’s easier to deal with people who smoke joints than with real criminals. They get very big budgets – the police, after all, are even against decriminalization, although they have no grounds for this other than the excuse that “this is how we catch dealers.” Do people who smoke have to be hostages of the police in order to catch drug dealers? Is the arrest of drug dealers useful in reducing the dimensions of the phenomenon?

What about the pharmaceutical companies?

I don’t have a smoking gun, of course, but there are hypotheses that the pharma companies are behind the super-slow progress being made in regard to medical cannabis. Its export has been bogged down for a few years [in Israel], and the prevailing conjecture, which to me sounds logical, is that the pharmaceutical corporations are behind this. Their interest is clear: They don’t want people to start using cannabis and then reduce or stop taking medications. So I see it as a mission: to free the public of its ignorance and to apprise it of the true facts.

There’s a petition to the court now, submitted by Green Leaf [a political party that advocates the legalization of cannabis] against the criminalization of marijuana, on the grounds that it violates the Basic Law on Human Dignity and Freedom. I was asked to write a professional opinion, and am doing so. It will be part of the petition.

What do you plan to say?

Naturally, I can’t reveal too much, but overall it’s about refuting mini-myths related to cannabis in order to persuade the justices that it’s not some monstrous substance that will lead to a disaster if the ban on its use is lifted.

Drugs and immigrants

Let’s talk about the process, which you address in your talks: namely, the gradual use of recreational drugs in medical treatment. You have a certain perspective on this, because the research you conducted ended a decade ago.

At that time people didn’t talk about cannabis like they do today. There were occasional experiments. Attempts were made to use cannabis in treating anorexia, for example, but it didn’t gain momentum. Today, drugs like these are used to treat a great many diseases and phenomena, after many years during which drugs were considered anathema. In the United States, the process of outlawing drugs began during Prohibition. Alcohol, after all, is a psychoactive drug in every respect, and that law was a reaction to massive immigration from Europe to the United States and to the culture of drinking in Europe, which the authorities very much did not like.

It’s interesting, by the way, that precisely at the stage when the prohibition on alcohol was lifted, the ban on cannabis began. The hypothesis is that the personnel who were in charge of enforcing the alcohol ban were left with no work to do, so they were sent to persecute cannabis users. Until the early 20th century, cannabis was legal and was even sold in drugstores. But when it arrived in the United States together with a wave of immigration from Mexico, it was outlawed. And it’s clear that economic interests were involved then, too.

What about psychedelic drugs?

Psychedelic drugs were very popular in South America and gradually penetrated the United States and the Western world overall. Aldous Huxley tried mescaline, and Timothy Leary, a professor [of psychology] at Harvard, conducted his famous experiment and aroused the fear and suspicion of the establishment. Leary’s experiment was halted and he became the darling of the hippies and of various proponents of the counterculture, who used LSD and mushrooms to the point where they became the very trademarks of the counterculture. Finally, LSD and the mushrooms were outlawed, which didn’t, of course, stop people from continuing to use them.

In our time we’re seeing the opposite trend: recognition of their medical qualities. Why is this so? Why now? Is the approach “Let’s try all existing substances until we find something”?

I can’t pinpoint the exact turning point when this trend started, but it certainly has to do with the discovery of the mechanisms of these drugs and their modes of operation. With cannabis, for example, until Prof. Meshulam discovered its active substances, no one knew what that it did, and that opened a window to a whole world.

In other words, the new conception derives from progress in brain research.

When it was discovered that psychedelic drugs work by activating serotonin, it was already known that illnesses such as depression are related to serotonin. So someone did the calculation that they might be useful for depression, too, but that really is progress made in the past few years. The psychedelic drugs specifically were like outcasts. They were feared because they generate hallucinations, and because most of them are synthetic. The objections to them were greater than for cannabis.

Let’s talk a bit about neural conduction. Roughly and simplistically, information in the brain is transmitted when one cell fires a chemical substance – a neurotransmitter – at another cell. It’s in that encounter, in the space between the cells in which the substance exists, that the influence of drugs occurs.

I like the analogy by which the chemical substance, the neurotransmitter, is like a key, and the receptor to which it attaches is a lock. Each key actually fits one specific lock, with the exception of a few substances that can attach to a number of receptors. Opening the lock causes electrical changes in the door that’s being opened. The drug can work on a particular neurotransmitter, it can inhibit the process of reabsorption into the cell that fired it, as in psychiatric medications; and cocaine and Ecstasy actually reverse the direction of the carrier, the substance that is responsible for returning the neurotransmitter to the cell that released it, so that instead of returning to the cell from which it was fired, it flows to the receiving cell, and thus its effect is prolonged.

The psychoactive drugs intervene in the process of neural conduction in the brain. They can alter it, intensify it or weaken it, extend or abbreviate its duration. Because neural conduction has a direct connection to our feelings, our consciousness, our cognitive functioning, it influences us, as well.

Reward and addiction

What about the reward system in the brain?

The reward system in the brain is actually intended to strengthen natural behaviors that are beneficial to our survival, such as sexual relations, which are critical for the species’ survival, or [a craving for] sweet foods that supply calories. All psychoactive drugs affect the brain’s reward system to one degree or another. Effectively, they deceive the system: We feel that we have done something that benefits us, even though in practice, of course, that’s not true. People use drugs to activate the mechanism by force, simply because that activation gives us pleasure even though it doesn’t serve any survival goal. The drugs trigger the reward mechanism – it signals us that we feel pleasure in the wake of the use of a drug, so we want to repeat the action over and over. That’s addiction.

So the question is not why to use drugs to try to gain relief or to cure mental problems, but why it took so long to arrive at this solution.

The answer is: cultural obstacles and vested interests. Conservatism. Across history, strange as it may sound, psychoactive drugs were not reviled. The ban is relatively new. The length of time in which cannabis, for example, has been prohibited is a tiny dot in our history, because there is evidence of its use going back thousands of years. All told, we’re talking about a hundred years, even less, since it’s been outlawed, but we’re brainwashed into thinking that this is natural.

And in contrast, psychiatric medications are considered totally legitimate and normative, even though in many ways their effect and the way they work are similar.

It’s only a matter of labeling. What’s the difference? A psychiatric medication is a chemical substance that affects the nervous system, and cannabis is a natural substance that affects the nervous system. In English the word “drug” also means medication – there’s no difference in the terminology. In Hebrew there’s a clear distinction [between sahm (drug) and terufah (medication)].

One of things I try to emphasize in my talks is that we need to free ourselves from the dichotomous division between drug and medication and from the mistaken working assumption that a medication is something good and a drug is something bad. All these substances affect our body in one form or another, they affect our functioning and our consciousness.

And in both cases we don’t know the full scope and consequences.

Correct. Opiod medications in the United States are simply killing thousands of people today. It’s ridiculous to think that they should be legal while cannabis isn’t. It’s really only a matter of convention.

Let’s turn to the use of psychedelic drugs for treatment of psychiatric problems. For example, ayahuasca, which has been found effective in the treatment of depression.

Ayahuasca is a herbal brew that was used by Native Americans for ritual purposes. It contains two relevant active substances. One works on serotonin receptors, the second effectively inhibits the breaking-down, thanks to which it’s possible to achieve a prolonged effect of the substance, after we drink it.

We should explain that the drinking of ayahuasca is a ceremony performed under the guidance of a shaman. I know a few people who have tried it. They described a psychedelic experience, hallucinations.

Yes. Obviously, the well-known ceremony was not performed as part of the clinical experiment that was done in a Brazilian university. The subjects, all of whom were suffering from depression and had not been helped by conventional medication, received either ayahuasca or a placebo under the supervision of the researchers. The experiment found that ayahuasca reduced the depressive symptoms, whereas the patients who received the placebo didn’t report any improvement – in fact, in some patients the depressive symptoms became even more acute.

But what was really interesting in that study was that a correlation was found between the intensity of the mystical experience, which was quantified through all kinds of questionnaires, and the improvement in the patients’ condition. The more powerful their experience, the more the depressive symptoms were weakened. That’s interesting, because in another study too, one that used psilocybin, which is produced by magic mushrooms, a connection was found between the intensity of the mystical experience and the level in the blood of a substance that is a product of the breakup of nicotine. In other words, the stronger the mystical experience, the less people smoked.

So there is a correlation between the intensity of the mystical experience and the therapeutic effect.

The conjecture is that the mechanism that causes the mystical sensations is also responsible for relief in the depressive symptoms. Of course, it’s impossible to prove the existence of a causal relationship.

Yes, but it can be assumed that there’s a connection to the release from the shackles of consciousness. The question arises of the degree to which consciousness creates the pathology.

These substances cause a blurring of the senses, liberation. They open the doors of perception, in the words of Aldous Huxley, and that allows us to be exposed to things and content that had been simply hidden from us. Brain scans done on people under the influence of LSD show that their whole brain lights up. There is very powerful activity, a great many regions in the brain are communicating with one another, the sensory experience changes.

Studies on LSD found that one of its effects is to dissolve the sense of the self – a Buddhist truth for liberation from suffering.

It’s not by chance that psychedelic drugs help in the treatment of mental illnesses more than other drugs. Cannabis also affects the physiological system, but with psychedelic drugs the effect on the body is minor; their primary influence is on the brain and on consciousness. Psychedelic drugs will not be used to relieve heart disease, say.

On the other hand, the description of heightened brain activity and a change in the sensory experience sounds similar to what happens in a psychotic attack.

I suppose that’s true – people undergoing a psychotic attack have powerful experiences, hear voices, see colors. That raises the question of whether psychedelic drugs are likely to aggravate schizophrenia or ease it. In any event, they are not used in cases of psychoses. Depression, in contrast, is not a psychosis, and psychedelic drugs can be used in an attempt to treat it. A study conducted in England tried to treat people suffering from depression that is immune to medications by means of psilocybin. The subjects underwent three brain scans in the experiment and immediately after the mushroom treatment. All of them reported a relief of the depression. The scans showed a change in brain activity.

That experiment examined long-term influences. How is it possible that it relieved the symptoms over time? After all, psychiatric drugs need to be taken daily.

That’s an interesting question, to which I don’t think they have an answer. We can only surmise. I find it hard to believe that the use of a drug caused a change in the brain chemistry, in the neurotransmitters. Possibly it’s a matter of dosage. The patients reported that it worked on them like a reboot of the brain. Despite the positive results, it was a preliminary study with a small number of patients, and we have to remember that this substance has side effects, so I wouldn’t recommend taking it just for the fun of it, and certainly if anyone wants to use it to relieve depression, that has to be done under medical supervision.

It’s interesting whether the patients themselves were able to overcome their prejudices about psychedelic drugs. It seems to me that when they’re used, the expectations shape the experience.

In indigenous cultures the psychedelic drugs are perceived as legitimate and are used in ceremonies and so forth. Western culture views them as something foreign, because they come from a foreign culture, and Western culture is not tolerant of anything that is “other.” Consider cannabis, for example, which was in widespread use in pre-Mandate Palestine, but under the British was added to the Dangerous Drugs Ordinance. Why? In my opinion, because they wanted to make it clear that they intended to impose a different culture here.

And the natives here are “drinking hashish” [reference to a line from the 1978 film “Lemon Popsicle”].

Yes. When the Spaniards arrived in South America they also banned the use of psychedelic substances, and for the very same reason. It’s something deeper and bigger than the approach to drugs as such – it’s an approach to what is different from you, something that doesn’t exist in your culture. The very definition of certain substances as “drugs” is a matter of culture. What is alcohol? Isn’t it a drug? Isn’t nicotine a drug? The word “drug” is used to indicate something that is foreign, not to say threatening, to our culture.

https://www.haaretz.com/israel-news...asca-is-like-a-reboot-for-the-brain-1.6431971
 
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Endocannabinoids in MS and ALS

Pryce, Baker

There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.

https://www.ncbi.nlm.nih.gov/pubmed/26408162
 
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A promising new medication for ALS

Experiments conducted on worms, zebrafish, mice and, finally, on human subjects in a limited clinical trial conclude that pimozide may be effective in treating ALS, or “Lou Gehrig’s disease.”

Researchers from the University of Montreal Hospital Research Centre (CRCHUM) and the Cumming School of Medicine (CSM) at the University of Calgary have discovered a medication that could make it possible to treat individuals with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.

An article published today in JCI Insight concludes that pimozide was found to be safe and over the short term, preliminary data shows that it could stabilize the progression of ALS. This neurodegenerative disease normally leads to a progressive paralysis of the skeletal muscles and, on average, three years after the onset of symptoms, to death.

“This medication alleviates the symptoms of ALS in animal models,” said Alex Parker, a CRCHUM researcher and professor at University de Montreal. “Riluzole and edaravone, the drugs currently used, have modest effects. Other studies must be conducted to confirm our results, but we believe that we’ve found a medication that may prove to be more effective in improving patients’ quality of life.”

From worm to man

The story behind the discovery began six years ago with a little millimeter-long nematode worm called C. elegans. In his laboratory, Parker genetically modified the worms so that they would exhibit aspects of the human form of ALS. Simultaneously, his colleague Pierre Drapeau did the same thing to another animal, the zebrafish, a tiny tropical fish only 5 centimetres long.

The two scientists obtained funding from the U.S. Department of Defense to test medications on these worms and fish born with ALS. “We sifted through a library of 3,850 molecules approved for the treatment of other diseases, and found a class of antipsychotic drugs that stabilize mobility in worms and fish,” said Drapeau, a CRCHUM researcher, professor at University de Montreal and principal investigator on the study. “Pimozide works especially well in preventing paralysis in fish by preserving the neuromuscular junction.”

Subsequently, University de Montreal Professor Richard Robitaille performed electrophysiological tests on mice in his laboratory and reached the same conclusion. Thus, pimozide was shown to maintain neuromuscular function in three different animal models: worms, fish and mice.

Pimozide: a well-known drug

At the annual ALS Canada Research Forum in 2012, the researchers met Dr. Lawrence Korngut, an Associate Professor at the CSM, member of the Hotchkiss Brain Institute (HBI) and Director of the Calgary ALS/Motor Neuron Disease Clinic. “Pimozide is a drug that has been well-known for 50 years,” the neurologist said. “It was approved for treating certain types of psychiatric conditions, like schizophrenia, and costs only 9 cents per pill. Other recent studies have shown genetic links between schizophrenia and ALS. The next logical step was to test it on human volunteers with ALS.”

In 2015, the first preclinical trial for ALS was launched in Canada with a small group of 25 patients who had ALS. Funding was provided by the Quirk family of Calgary, by the HBI, and the Clinical Research Unit at UCalgary.

“We found the highest dose most likely to be tolerated in individuals with ALS – a lower dose than that used in other conditions – and we have preliminary proof showing that pimozide may be useful,” said Korngut.

The initial clinical trial was modest in scope. But after only six weeks, the researchers had a first indication of the drug’s efficacy. Loss of control of the thenar muscles, located in the palm of the hand between thumb and index finger, is usually one of the first signs of ALS. For patients who took pimozide, this function remained stable. This observation is tempered by the very limited size and length of the clinical trial.

“For us, this is an indication that we found the right therapeutic target,” said Drapeau. “Pimozide acts directly on the neuromuscular junction, as shown in our animal models. We don’t yet know whether pimozide has a curative effect, or whether it only preserves normal neuromuscular function to at least stabilize the disease. This is also the first time that a potential drug for human patients was discovered based on basic research on small organisms such as worms and fish.”

The next step: a phase II clinical trial

Now comes the next step: a phase II clinical trial on 100 volunteers, funded by the “The Ice Bucket Challenge” through a partnership between ALS Canada and Brain Canada to begin in the next few weeks. Headed by Korngut in Calgary and conducted in nine hospital centres across Canada, the study aims to confirm that pimozide is safe and to measure, over a six-month period, its effect on the progression of the disease and its symptoms and on patients’ quality of life.

Daniel Rompre, 47, father of two teenage girls, hopes to participate in the new study. He was diagnosed with ALS in March 2016. The muscles of his upper body are getting weaker, he is beginning to have trouble speaking, and he can no longer use his left arm. “It is hard to maintain a positive outlook,” Rompre said. “You ask yourself: ‘Why me?’ But at least it’s encouraging to see that research is advancing. There has been more progress in the last five years than in 100 years of research on the disease.”

It is too soon to draw firm conclusions about the safety and efficacy of pimozide. “At this stage, people with ALS should not use this medication,” Korngut emphasized. “We must first confirm that it is really useful and safe in the longer term. It is also important to be aware that pimozide is associated with significant side effects. Therefore, it should only be prescribed in the context of a research study.”

About the pimozide clinical trial

The recruitment of patients for the phase II clinical trial, “A Clinical Trial of Pimozide in Patients with Amyotrophic Lateral Sclerosis (ALS) (Pimozide2)” began on October 16, 2017. Funded primarily by ALS Canada and Brain Canada, the study is registered at clinicaltrials.gov (NCT03272503). The trial is headed by Dr. Lawrence Korngut at the University of Calgary, with the collaboration of nine hospital centres in Canada.

http://www.innovationtoronto.com/2017/11/lou-gehrigs-disease-or-als-may-have-a-promising-medication/
 
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ALS drug shows success in clinical trials

IFLScience | 20-Nov-2018

A drug to treat Motor Neurone Disease (MND) – also known as amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease – appears to have dramatically slowed the diseases' progress in Phase I clinical trials. The scientists responsible are keen to stress the trials' limitations and say they “don't want to add to the hype”, but the work certainly marks one of the most encouraging developments in the fight against the disease that killed Stephen Hawking we have seen.

For people with MND, respiratory failure is the most common cause of death. So the announcement at the 29th International Symposium on ALS/MND that 32 patients given the drug CuATSM showed significantly less decline in lung capacity than beforehand is very important.

The trial's participants had very mixed rates of progression and time since diagnosis, forming a fairly representative sample. Many were also suffering cognitive decline prior to being put on the drug. This also stabilized significantly. A trial like this isn't designed to quantify effects, but disease progression apparently slowed by more than half.

Dr Kevin Barnham of Melbourne's Howard Florey Institute stressed to IFLScience the trial had no control group, so the comparison could only be with the patient's own rate of decline beforehand. It also lasted for just six months, so we don't yet know if the benefits are sustained.

Considering the best existing MND drugs only extend life by 2-3 months, however, these results are easily good for Collaborative Medicinal Development, the company developing CuATSM, to begin enrolling people in a double-blind Phase II trial to start later this year.

The story of CuATSM is an excellent example of the far from linear way science progresses. Fifteen years ago Barnham was part of a group of scientists were toying with the theory that copper had an important part to play in the development of Alzheimer's disease. Barnham told IFLScience they designed a drug that could cross the blood-brain barrier and alter the movement of copper. For a control, they needed a similar drug.

CuATSM was that control. Having used it in an animal trial, the team wondered if they could find any other applications. Drugs that cross the blood-brain barrier are quite rare, and CuATSM has anti-oxidant properties, which raised the possibility it might protect brain cells from damage. Barnham had worked on MND and, going on what he calls “a hunch” tried giving CuATSM to animals with the disease.

When it came to MND, CuATSM's effects in animals were impressive, although Barnham told IFLScience he and his colleagues are still debating the mechanism. The results for Parkinson's models were also sufficiently encouraging that Collaborative Medicinal Development has a second Phase I trial currently underway. However, animal trials showed no benefits for Alzheimer's, the disease against which CuATSM was originally designed.

https://www.iflscience.com/health-a...isease-drug-shows-success-in-clinical-trials/
 
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Eleusis

Role of the Sigma-1 receptor in ALS

Timur Mavlyutov, Lian-Wang Guo, Miles Epstein, Arnold Ruohoa

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease primarily targeting spinal cord motoneurons (MN). ALS can occur due to genetic mutations or environmental factors. Familial cases represent only about 10 percent of ALS cases and these are linked to mutations in particular proteins that eventually result in dysfunction and death of MN. Usually ALS is diagnosed in humans after the age of 40, but in some cases it can occur in juveniles. There is no cure for ALS and the best known protector, riluzole, which, in part, reduces levels of the excitatory neurotransmitter, glutamate, from neuronal synapses can only extend human life for a few months.

The Sigma-1 Receptor and neurodegenerative diseases

The Sigma-1 Receptor (S1R) chaperone protein has been shown to be a target for the treatment of a variety of chronic neurological diseases including Alzheimers, Parkinsons, and Huntington's Disease. Recently, ALS was added to this list. It is remarkable that MN express S1R at the highest levels in the CNS. Mutations of the S1R have been found to result in the establishment of ALS in humans. In contrast, genetic knockout of the S1R in mice did not produce an ALS phenotype. S1R knockout mice on an ALS background, however, showed a faster onset of disease and decreased longevity while application of S1R ligands significantly extended the lifespan of ALS model mice.

The Sigma-1 Receptor, Indole(ethyl)amine N-MethylTransferase (INMT) and N,N-Dimethyltryptamine (DMT)

Several endogenous compounds have been shown to bind to the S1R and thus may provide regulation of S1R activities. Although the affinity of these compounds for the S1R varies considerably, activation of the S1R may depend on the cellular environments and the local concentrations in various mammalian tissues. We have shown that DMT is an agonist for the S1R. The relationship between DMT and the S1R was further reinforced by the demonstration that the enzyme, Indole(ethyl)amine N-methyltransferase (INMT) that converts the amino acid tryptophan decarboxylation product, tryptamine, into DMT, co-localized with the S1R in C-terminals of the primate MN. This paradigm shifting observation of co-localization of S1R and INMT to produce DMT, may be functionally very important to provide high local concentrations of the agonist due to the close juxtaposition with the S1R.

Studies demonstrate and propose new biological roles for DMT, which may act as a systemic endogenous regulator of inflammation and immune homeostasis. According to these new results, DMT and 5-MeO-DMT possess the capability to inhibit the polarization of human moDC-primed CD4+ T helper cells toward the inflammatory Th1 and Th17 effector subtypes in inflammatory settings. The mobilization of innate immune mechanisms is also well established in many psychiatric and neurological disorders. Thus, as a target for future pharmacological investigations, DMT emerges as a potent and promising candidate in novel therapies of peripheral and CNS autoimmune diseases such as Multiple Sclerosis, Amyotrophic Lateral Sclerosis and cancer.

https://www.sciencedirect.com/science/article/pii/S1347861314000346
 
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Potential therapeutic target for ALS identified

Harvard University | January 15, 2019

Discovery opens doors to improving diagnostics and developing new therapy for majority of ALS patients.

New research has revealed that the protein TDP-43 regulates a gene called Stathmin2 (STMN2). STMN2 shows promise as a therapeutic target and could be the first biomarker ALS, which is extremely difficult to diagnose and treat.

Patient specific stem cell-derived motor neurons stained for the neuronal marker III-Tubulin (green) and the ALS-implicated protein TDP-43 (magenta). In this study, the authors determined that TDP-43 sustains normal levels of the microtubule destabilizing protein STMN2, which helps neurons grow and regenerate axons.

Research led by stem cell scientists at Harvard points to a potential new biomarker and drug target for ALS, a neurological disease that is extremely difficult to diagnose and treat. Published in Nature Neuroscience, the study used stem cell models of human motor neurons to reveal the gene STMN2 as a potential therapeutic target, demonstrating the value of this human stem cell model approach in drug discovery.

Diagnosing and treating ALS

Patients with ALS experience the loss of motor neurons and progressive paralysis. Following a long diagnostic journey, they may survive up to five years. Two ALS drugs have been approved by the U.S. Food and Drug Administration (FDA), but they act only to slow the disease.

In addition to a cure -- or even a treatment that is effective for more ALS patients -- a robust test for ALS is sorely needed. For that to happen, scientists need to find a reliable biomarker of the disease.

TDP-43: a hallmark of ALS

Ten years ago, scientists found aggregates of a protein called TDP-43 in post-mortem neurons from ALS patients. This protein should have been in the nucleus of those neurons, but instead it was being flushed out, and building up in the cytoplasm.

Clearly, some of the genes at work in the trash-disposal system of neurons (called the proteasome) were interacting with TDP-43 in a way that led to ALS. But which genes are involved, and what they are doing, has not been known.

The gene that encodes for TDP-43 can be mutated to trigger ALS. It is passed on to future generations, who then develop either ALS or, in some cases, frontotemporal dementia (FTD). Since TDP-43 aggregates were discovered in ALS patients, they have been well known as a hallmark of the disease.

What the researchers did

TDP-43 is one of many proteins that binds to RNA, which is responsible for transmitting genetic information and translating it into a concise recipe for a given protein, for example part of a growing neuron.

The researchers set out to identify, for the first time, all the possible types of RNA that are regulated by the TDP-43 protein in the context of human neurons. Until now, studies like this have only been carried out in mice and cancer cell lines.

Then, they looked at what happened to each gene when they manipulated TDP-43.

What they found

The researchers reduced the levels of TDP-43 protein in human stem cell-derived motor neurons. Then, using RNA-sequencing, they analyzed how gene expression changed in these cells.

Among the thousand or so genes that changed when TDP-43 was manipulated, one stood out: Stathmin2 (STMN2), a gene that is important in neural outgrowth and repair. STMN2 changed consistently in step with TDP-43.

"Once we had a connection between the TDP-43 and the loss of this other critical gene, STMN2, we could see how a motor neuron might begin to fail in ALS," said Joseph Klim, postdoctoral fellow in the Harvard Department of Stem Cell and Regenerative Biology (HSCRB).

"With the discovery that our human stem cell model had predicted exactly what was happening in patients, Joe went on to test in this system whether fixing Stathmin2 could rescue the motor neuron degeneration in our dish caused by disturbing TDP-43. In a beautiful series of experiments that I believe provide great hope for patients, he went on to show this was exactly the case: rescuing expression of Stathmin2 rescued motor neuron growth," said Kevin Eggan, Professor of Stem Cell and Regenerative Biology at Harvard.

The culprit

The researchers observed that without TDP-43, STMN2's perfectly read protein-making instructions turn into nonsense.

"We discovered that when TDP-43 levels are diminished in the nucleus, a cryptic exon is spliced into STMN2 messenger RNA. That basically deletes its instructions for making functional protein," explained Klim. "It becomes impossible for STMN2 to create a vital component for repairing or growing motor neuron axons."

Double- and triple-checking

The next step was to see if their findings reflected the reality of a patient's biology. They obtained data from RNA sequencing studies that used post-mortem samples from ALS patients. Those rare datasets, compared with controls, echoed the team's original findings in human stem cell models. The data from ALS-patient spinal cords mapped to the cryptic exon, but data from the controls did not.

Luis Williams of Q-State Biosciences, whose Ph.D. thesis in HSCRB was the first major step in this study, added, "Because we had pluripotent stem cells of human origin, we could make cells in a dish that are relevant to ALS and investigate this very specific problem in the right context: with a human genome and all of the genetic factors that regulate motor neurons."

Why it matters

"These experiments point towards a clear path for testing whether repairing Stathmin2 in patients can slow or stop their disease," said Professor Eggan. "The discovery we have made suggests a clear approach for developing a potential therapy for ALS -- one that would intervene in all but a very small number of individuals, regardless of the genetic cause of their disease."

https://www.sciencedaily.com/releases/2019/01/190115162311.htm
 
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Therapy approved for Parkinson’s has potential to treat ALS

by Marta Figueiredo | Aug 31, 2018

Requip (ropinirole), a medication already approved to treat Parkinson’s disease, may be a potential therapeutic agent for amyotrophic lateral sclerosis (ALS), according to a preclinical study.

The study, “Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent,” was published in the journal Nature Medicine.

Most cases of ALS (90-95 percent) are considered to be sporadic, with only 5-10% of cases inherited, or familial. The sporadic nature of the majority of cases of ALS makes it difficult to create models of the disease, and to identify disease-causing genes and potential therapeutic compounds.

As a result, while a dozen mutations have been shown to cause familial ALS, such as in the SOD1, TDP-43, and FUS genes, the causes of sporadic ALS are largely unknown.

However, increasing evidence has pointed to the existence of several common features between sporadic ALS and non-SOD1 familial ALS — such as those affecting the TDP-43 or FUS genes — suggesting that compounds suppressing these common features may represent new therapeutic agents for a wide range of ALS patients.

Japanese researchers evaluated the therapeutic effects of selected compounds in a variety of ALS cases through the establishment of sporadic ALS models.

They generated motor nerve cells from induced pluripotent stem cells (iPSCs) — stem cells derived from differentiated cells that can virtually generate any cell type in the body — of 32 sporadic ALS patients.

These cells were able to mimic the patients’ genetic and clinical diversity in vitro, making them successful cellular models of sporadic ALS.

“We clearly demonstrated that iPSC technology enabled the generation of elaborate disease models that accurately reflect the clinical features of genetic conditions, even sporadic diseases,” the researchers wrote.

An analysis of the therapeutic effects of more than 1,000 approved medications in non-SOD1 familial ALS models, as well as the compounds’ serious side effects and ability to cross the blood-brain barrier — a protective membrane that restricts the passage of large molecules to the brain — pointed at Requip as the best potential therapeutic agent.

Requip, an anti-Parkinson’s medication, acts as a substitute for dopamine in the brain. Dopamine is an essential chemical messenger between nerve cells that recent studies have suggested is a regulator of motor nerve cell function.

Adding Requip to the sporadic ALS models was found to suppress cell death, abnormal protein aggregation, nerve cell atrophy, and the production of oxygen-related damaging molecules in most of the models.

While the majority of the sporadic models that responded to Requip showed similar features to TDP-43– and FUS-familial ALS models, those that did not respond had a gene expression profile more similar to SOD1-familial ALS models — which were also non-responders.

These findings highlight the potential of Requip to treat a diverse range of ALS cases, both familial and sporadic.

Additional analysis of the changes in gene activity induced by Requip showed the involvement of inflammation — fat degradation — and dopamine-related pathways.

These results support the use of this approach to generate sporadic ALS models, better understand the mechanisms behind specific cases of ALS, and identify new therapy candidates.

The team noted that this approach may be applied to other sporadic neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease.

https://alsnewstoday.com/2018/08/31...pproved-parkinsons-therapy-preclinical-study/
 
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It hurts to read some of this stuff because my father was diagnosed with ALS 6 years ago. He's still alive, but for years he's been almost entirely paralyze... now he is like Stephen Hawking basically, and he is absolutely suffering and miserable 100% of the time, it's horrible. Even if he did something now to stop it, when the damage is already done, he would consider that a fate worse than death. Unfortunately my father is really against taking "drugs" (which means recreational drugs, which means to him, not even weed which has been legalized). My brother and I tried really hard to get him to start taking CBD years ago, before it had gotten bad, we even got our mom on our side. He resisted though until it got legalized in their state, and the disease had already progressed substantially. Then he tried it for a week and said it wasn't working and stopped. The idea of using ayahuasca to actually stop or at least help the disease is something he would never do. It's very likely that if this had happened 10 years from now, he would have jumped at the chance. I'm so excited that psychedelic research is finally unfrozen and happening with increasing gusto, because I think there is so much potential for healing there. The decades of research from the 50-70s that got mostly suppressed and buried agrees with that, too.​
 
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Transplanted human bone marrow cells hold promise as ALS therapy

by Jose Marques Lopes | April 5, 2019

With amyotrophic lateral sclerosis (ALS) improved their motor function and preserved motor neurons by repairing the barrier protecting the spinal cord.

The study with that finding, “Human Bone Marrow Endothelial Progenitor Cell Transplantation into Symptomatic ALS Mice Delays Disease Progression and Increases Motor Neuron Survival by Repairing Blood-Spinal Cord Barrier,” was published in the journal Scientific Reports.

The blood-brain and blood-spinal cord barriers (BSCB) are composed of endothelial cells, pericytes, located along the walls of tiny blood vessels called capillaries, and processes derived from astrocytes, a cell type also involved in the response to injury.

Increasing evidence has linked impairments in each of these components to ALS, both in patients and in animal models. Disrupted barriers allow the entry of immune cells and other potentially harmful substances from the blood circulation, which may aggravate degeneration of motor neurons — specialized cells that control muscle contraction — a hallmark of ALS.

In mice with ALS, the team at University of South Florida in Tampa previously showed that human bone marrow cells containing the CD34 marker (hBM34+) may be a therapeutic stray for ALS, as they delayed disease progression, preserved motor neuron survival, lessened a marker of reaction to injury, and maintained barrier integrity. The transplanted cells differentiated into endothelial cells — those that line blood vessels — and nested in capillaries of the spinal cord.

A subsequent study in the same mouse model, G93A, revealed that a high dose of transplanted cells restored the fine structure of capillaries and stabilized their density in the spinal cord, while also improving myelin integrity. (Myelin is the protective layer that insulates the nerves.)

As noted in a press release, although these findings support the use of such cells to repair the BSCB and improve ALS-related alterations, the most significant effect of hBM34+ cells on motor function was determined at four weeks after transplant. Also, a substantial damage in spinal cord capillaries was detected even after high-dose treatment.

This made the team test whether human endothelial progenitor cells (EPCs) — bone marrow-derived, but more similar to endothelial cells than undifferentiated stem cells — would provide superior BSCB restoration in G93A mice.

At two to three weeks after transplant via intravenous infusion, mice given EPCs from adult donors showed significantly higher body weight, improved motor function and slowed disease progression than controls with ALS, as assessed by extension reflex scores, grip strength, and motor coordination.

At four weeks, these mice also demonstrated BSCB repair associated with widespread attachment of EPCs to capillaries in the cervical and lumbar spinal cord and in the brain’s motor cortex and brainstem — two regions known for motor neuron degeneration.

Other improvements in the cervical and lumbar spinal cord included restored capillary and pericytes’ structure, normalized astrocytic processes, less leakage into the spinal cord, and extended survival of spinal cord motor neurons. This was reflected by signs of degeneration in only a small subset of motor neurons and by higher number of these nerve cells than in controls with ALS.

Cautioning that further studies are needed, the team commented that “from a translational viewpoint, the initiation of cell treatment at the symptomatic disease stage offered robust restoration of BSCB integrity and shows promise as a future clinical therapy for ALS.”

 
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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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Allegheny Health Network

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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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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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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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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