Jean-Pierre Le Rouzic
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Cognito Therapeutics has delivered clinical data from its digital treatment for patients with Alzheimer’s disease—which relies on light and sound to stimulate specific electrical frequencies in the brain’s neurons—showing it helped improve memory and cognition as well as physical symptoms.
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You can find here my detailed analysis of this paper, you could jump to (my) conclusions.
I think that there is some potential here, but what strikes me the most is that they should have studied astrocytes because when a drug seems to affect only the UMN and not LMN, it is much more probable that it is the astrocytes that they affect.
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It looks like a therapy to degrade TDP-43. Since 2019 there were some experimental therapies. Initially the vehicle for the drug was a virus (i.e. a genetic therapy) but more recently the bearer was a peptide (for example having a TAT sequence) or similar mechanisms like PROTAC.
It’s interesting times, different teams are converging toward the same kind of therapy. But this does not mean a drug will appear tomorrow, several years and a few $M are necessary to make it a drug accessible on the market.
I think this kind of therapy will be able to stop the progression, but not reverse the disease, because many motor neurons have already died when one is diagnosed, and motor neurons do not regenerate. (but there are teams working on that last problem)
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From their abstract:
“This suggests that the improvement in muscle strength observed in the stimulated arm is unlikely related to reinnervation. ”
So the authors did not expect it to be a breakthrough.
Dagmar convinced me that a gentle exercise is actually good for ALS patients (which I am not).
That, and keeping a BMI at 27. A newly diagnosed ALS patient needs a lot more calories than a healthy person:
https://padiracinnovation.org/en/ALS/weight.html -
I am really excited!
Scientists, including one with which I corresponded last year have develop a peptide to target and degrade α-synuclein in Parkinson disease.
The peptide is assembled with the TAT sequence, a sequence specific to α-synuclein, and a sequence signaling degradation to the proteasome. See the previous discussion for more info.This time it is the seventh study on the topic of using peptides to remove a misfolded protein in a neurodegenerative disease (ALS, Alzheimer, Parkinson).
I know that another scientist in Australia is working on using a PROTAC (a very similar technology) to target TDP-43.It’s very easy to imagine that the same technology would apply to TDP-43, so it is probably a matter of months before it is done.
You can find a summary of Nature biology’s article on my website.
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Light bulbs are powered with alternating current at 60Hz in USA and some parts of Asia, and 50Hz in other parts of the world. It would not be hard to power them in 40Hz.
A device powering small power LEDs is available on Amazon.It seems also that it works to some extend with sounds, there is a good recap here.
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Thanks, it’s an impressive list!
Sometimes there are ALS related articles on ALZforum.
There used to be a collaboration between ALZforum and Prize4Life’s ALS research forum.
However ALS research forum disappeared in 2019.
I kept an incomplete copy of ALS research forum on my website. -
Shameless self promotion: In 2019 I wrote a book about the state of ALS research.
I am not a MD, I am a R&D engineer in Telecoms, but for personal reasons I feel too little had been done in ALS research.
Sadly not much interesting occurred in ALS research in 2020.
It is a long book with many references but I will make an update probably at the end of January 21, after the publication of Arimoclomol results.
The new book will be updated with recent clinical trial results. It will be easier to read, both because sentences will be simplified (English is not my native tongue), but also because I was a bit angry at the time, now hopefully I could make a better job.If you are still interested here the link for the current book, but you should wait until it is updated.
Jean-Pierre
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I did not check the video but there is a funny story about mouse poop at Alzforum.
To simplify an ALS mice model at Harvard get ill while the same animal model is healthy in MIT or Jackson labs.
The reason? If we listen the scientists, it is perhaps because mice’s gut microbiome is different at Harvard.
However mice are notoriously extremely sensitive to their carers, a mouse that feels it is loved is usually healthier.
If instead you want to be very serious, look at Braak stages for Alzheimer and Parkinson. It may apply as well to ALS but it was never seriously investigated. Oddly it’s an old stuff … 2003, that seems to have been rediscovered recently.
Jean-Pierre
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Something related to my CERF possible proposal, as in both cases the goal is to destroy molecular aggregates (misfolded aggregates TDP-43 in my case):
Faze Medicines, a biotechnology company pioneering therapeutics based on biomolecular condensates, announced its launch and Series A financing of $81 million. Faze is founded by leading experts in the emerging field of biomolecular condensates with the mission of leveraging this fundamentally new understanding of cell biology to develop therapies to slow, halt or reverse disease pathology.
The Series A will support Faze’s preclinical research in two initial therapeutic focus areas – ALS and myotonic dystrophy type 1 (DM1) – as well as research to explore condensate biology in other disease areas. In ALS and DM1, a robust body of literature points to a causative role for condensate dysregulation. Leveraging state-of-the-art screening and proteomics techniques, Faze will identify proteins that are key components or regulators of disease-causing condensates, and then employ proprietary assays to discover small molecule drugs targeting these proteins.
I wrote a longer article about Faze Medicines on my web site.
Jean-Pierre
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Some news:
The CERF prize received groundbreaking innovations from the foremost medical scientists and engineers in the world, not to mention some incredible submissions of work from teams previously unknown from them.There are both engineering solutions to improve function, and medical/biological solutions to improve function and survival. So they have decided to offer two separate prizes; one for engineering solutions to improve function, and one for medical approaches to improve both function and survival.
The applications should be sent by March 31st 2020.
Please, if you are a stakeholder in a laboratory interested in a therapy for ALS based on CPP or similar technologies such as PROTAC, ask them to join my initiative.
People can email me at [email protected].
Best regards from France,
Jean-Pierre
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The results of the phase III of Nurown are out and they are similar to the phase II.
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Dagmar, I like your reaction to this type of news.
Meta studies in any domain are mostly junk studies.
The people doing this kind of studies do not care to access to the original datasets, they just read the conclusions of the original studies and accumulate the number of participants in the original studies to have impressive numbers, but really it is just hot air. There is no substance to that kind of studies.Another thing is that each year there are 15,000+ scientific articles about ALS only. But each year there are only perhaps 30 or 40 articles that have some interest, and perhaps one article per year which is a breakthrough.
The way our society do science is very inefficient.
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There were two people diagnosed with ALS in my family. The ALS clinic (in France) provided only minimal services or information.
After two years studying ALS research papers, I am not even sure that familial ALS means something related to some of the 126 “ALS genes” [0].
In my opinion “inheritable ALS” does not means that there is an “ALS gene”, even in the case of C9orf72 (which is anyway an ORF [1], not a gene).
My opinion is that clinical trials have too stringent rules for diseases like ALS, as past phase III clinical trials have been declared failed for drugs that brought some improvement, unfortunately at the cost of side effects.
It would have been better to try to mitigate those side effects, than to stop the research entirely (usually if a phase III failed it is very difficult for a biotech to fund further research).
Caveat lector: I am not a doctor nor a scientist.[0] https://alsod.ac.uk/
[1] https://en.wikipedia.org/wiki/Open_reading_frame -
In every person, bloating may be caused by a digestion problem: If your gastrointestinal tract has difficulties to process food containing carbohydrates, then bacteria that colonize the GI tract will process them, and unfortunately they produce gas in doing so [1].
A personal hypothesis (I am not a doctor): May be for pALS using a feeding tube some digestive enzymes from the saliva glands are missing [2], so this new ecological niche was filled with opportunistic bacteria.I am not sure if there is a quick fix to this problem.
[1] https://www.niddk.nih.gov/health-information/digestive-diseases/gas-digestive-tract/symptoms-causes
[2] lingual lipase, salivary amylase, lysozyme
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I do not know this platform but it seems under Merit Cudkowicz supervision.
As I read daily new research on ALS, I can assure you that she is someone who did a great contribution to the field.
She is probably one the 10 best US scientists in the area of ALS.Jean-Pierre
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Thanks David, I really appreciate.
There is a French version, it is also available as an ebook :
https://www.amazon.fr/dp/B082R7BC8HInitially I planned to publish an updated version in October. But so far 2020 had not been very prolific on the ALS research front. I look forward at the results from the clinical studies of Arimoclomol and NurOwn, so maybe the updated versions will be available in February 2021, hopefully with good news.
I am also happy that in 2020 ProMIS neurosciences designed intrabodies against TDP-43 granules. I am still waiting for biotech to propose a genetic therapy against TDP-43 cytosol granules. This is not a scientific or technical challenge, it is essentially a funding problem. -
I agree with you Kasper, particularly about the risk that no insurer will pay so much.
This reminds me about Glybera, it was a gene therapy treatment designed to reverse lipoprotein lipase deficiency (LPLD), a rare inherited disorder which can cause severe pancreatitis.
https://newsinteractives.cbc.ca/longform/glybera
Its cost was $1 million in 2015, making it the most expensive medicine in the world at the time. In 2012, the European Commission approved Glybera, but only one person was treated with Glybera and at the end the biotech went bankrupt and 8 years later there is still no approved drugs for LPLD. Mostly the costs were due to bureaucracy.
What is strange is that a few scientists claimed that the cost of production of this drug were actually only a tiny fraction of 1 million. Last year they made a proof of concept with only $7000.
https://www.scihouse.space/scihouse-goes-to-biohack-the-planet-2019/But the scientists that created Glybera told that this low cost is unrealistic as it does not take in account the cost of training medical staff around the world nor distributing the therapy through secure channels that themself are very costly.
In turn I find this critic not very realistic, as the disease is even more rare than ALS, they could have sent the patient (who often were not disabled) to one clinic, instead of trying to send to drug close to the patient. Even in cancer there is something similar. A new therapy is CAR-T, if a patient in Europe is treated with this therapy, cells are extracted from the patient, sent over the Atlantic, processed in US and sent back in Europe. Does this serves the patient (and insurer) interests?
I suspect that the new trend high cost of drugs in general is similarly not due to real costs, but is set to the highest price that insurers would pay. It was recounted that this was how Zolgensma was priced.
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I am not a doctor, but I think that Nurown is the fruit of a line of research which is valid: How to administrate neurotrophic factors where they could be useful.
Nurown is certainly not the final cut in this line of research, I expect new therapies to be more effective and/or easier to administrate. Intrathecal administration is not fun at all, and probably Nurown will be needed every few months. On the long term it might be risky.
What we need is a therapy which is easy to tolerate by the patient, that can not only stop the progression but also enable people to recuperate their previous health.
– To stop the progression I only see genetic therapies with intrabodies targeting TDP-43 such as what the group of Jean-Pierre Julien in Canada or the group of Makoto Urushitani in Japan are studying. Therapies with neurotrophic factors are not designed to achieved that.
– To recuperate pALS’s previous health is not something which can be done easily. People older than 70 yo that have not moved for 5 years (for example after a spine accident) cannot recuperate even with therapies that are helpful with young people that are treated just after the accident. Neurotrophic factors may help here.
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Hi Dagmar,
“Did the researchers look at if the high LDL levels were present prior to diagnosis?”
To try to answer this question, the scientists did not check people with ALS directly. What the scientists did in this study was comparing large sets of genomes expression (GWAS), one obtained from healthy people and the other from people being diagnosed with ALS. They did that for European and Asian people.
The rough idea is that if a gene is expressed in the disease but not in the healthy genome, then there is some relation between the gene (or protein) and the disease. But this technique is not enough powerful to isolate only a few causal relations.
In addition they did what is called Mendelian randomization. Mendelian randomization helps to find only a few factors that really causative and not some random coincidence.
“Perhaps the process of early ALS in the body causes LDL levels to rise once the disease is established?”
LDL rises when the liver has processed increasing amounts of glycerol and fatty acids. Glycerol and fatty acids are processed by our body when it needs more energy, the energy in excess is stored as fat.
I have the impression that nobody can answer your question at the moment. What seems to me is that more and more things hint at ALS as a metabolic disease. What I mean by that is that cells and particularly motoneurons, need a lot of energy. I suppose (but some scientists already told that) that when there is some event that impair the capacity of the body to deliver this energy, then the cells fail. Some of those event has been hinted by some scientists as maybe defective genes such as mutation in SOD1 or C9orf72, which makes the cell having to use other mechanisms to repair the proteins, hence using more energy that usually. My personal guess is that also happens with infection or when the body is harmed. But at the moment nobody knows the etiology of ALS.
In conclusion, I would say that Mendelian randomization is a great investigative tool, that is as powerful as clinical research to assert if there is some causal relation between a protein and a disease. And it is about humans not mice, so it can be translated more easily in drugs.
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I think we have a limited vocabulary to describe this new situation so it is difficult to express our thoughts.
In my opinion Dagmar is right to talk about little exercises like learning new tricks to move the body and adapting to the new ALS life. What is probably important is the complexity of the activity and not its energy consumption.
The reason I see is that complex activities like dancing or swimming are actually involving the upper neurons. Lower motor neurons are involved in more basic biological functions involving speed and strength. Muscles use a lot of energy and the energy supply is limited in ALS so it must not be wasted.
If there is a way to preserve upper neurons by activities such as what Dagmar suggests, then it is a sort of breakthrough in ALS. Dagmar IMO you should try to think more about this, how to involve upper motor neurons with complex activities without using much energy and adapted to limited motor capacity, all would benefit.
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In my opinion, for now Nurown worth the pain inherent to its administration and it should be administrated every few months. Arimoclomol is probably something more easier to prescribe to patients (and hopefully less costly) as it does not mandate a special medical procedure and has a clear and understandable mechanism.
Apart from that there are Canadian and Japanese groups that are designing therapies. These are the things that at the moment are closest to a cure but they are not yet ready for clinical trials.
To paraphrase Feynman I would stay away from people making extraordinary claims without extraordinary evidence.
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Hi Angelique,
I am sorry for you and your family.
1) There are some research on FUS gene mutations. For example look at the following link, those scientists are in Belgium, so not far from the Netherlands.
2) I am not sure there is a better support in US than in Western Europe (for example there are many great people in Ulm).
3) see point 1
4) Nurown is a genetic therapy that makes CNS cells secreting neurotrophic factors (it helps failing neurons), while not perfect it could be used by all ALS patients.
My best wishes
Jean-Pierre