Jean-Pierre Le Rouzic
Forum Replies Created
-
There is no reason that this drug is not moved up and approved now by the FDA for ALS?
I do not understand how data is impressive?
If you look at the figure 2 in the scientific publication you will see that there is a 3% difference between placebo group and groups that received Masitinib. each group contained ~30 patients, so I guess this is just a statistical fluke.
Basically they took the results from a past clinical study, selected only patients who had a small decrease in ALSFR and then found that those patients survived longer. Is this really surprising? Does it really support the idea that the drug should be administered early to patients?
-
There is no reason that this drug is not moved up and approved now by the FDA for ALS?
John, I do not understand what data is impressive here.
If you look at the figure 2 in the scientific publication you will see that there is a 3% difference between placebo group and groups that received Masitinib. each group contained ~30 patients, so I guess this is just a statistical fluke.
Basically they took the results from a past clinical study, selected only patients who had a small decrease in ALSFR and then found that those patients survived longer. Is this really surprising? Does it show some efficacy in this drug? Does it really support the idea that the drug should be administered early to patients?
There is a recent opinion piece in BMJ (after many similar opinions in Nature’s Journal) that we should consider the result of each clinical trial as fake until it is replicated by independent investigators.
-
Thanks John,
Nutrition is indeed of the utmost importance for pALS.
There are several calorie calculators for pALS, including on my website padiracinnovation.org
They are based on the work of Dr. Edward Kasarkis, Medical Director at the University of Kentucky. -
There are bizarre and interesting stories on this topic, for example the mice animal model of C9orf72 that dies quickly at Stanford but where perfectly healthy at MIT.
After investigating the matter, the scientists (including Dr. Eggan) found that the mice didn’t have the same gut microbiome.
https://www.alzforum.org/news/research-news/gut-microbes-difference-between-life-and-death-c9orf72-mice -
Thanks Dagmar for researching some simple and easily comprehensible text on what is ALS, but I find this specific text extremely imprecise and confusing about what scientists know about ALS. And it lacks to tell about some areas, for example the genetic background.
> ALS is a heterogeneous disease,
There is no real diagnosis of ALS. It’s only a differential diagnostic: When one has motor troubles and muscle wasting, and when it’s impossible to diagnose another disease, then someone is told they have ALS. Is there really a single disease named ALS? If there is no clear single ALS disease then saying it’s a heterogeneous disease is true but not very helpful.> Axon Structure and Dynamics
Most ALS scientists think along the “dying forward” hypothesis which postulates that ALS (like Parkinson or Alzheimer) starts in the brain, specifically in the motor area where are the bodies of upper motor neurons. If that’s true, and it’s the most common statement, then it has nothing to do with axons, and specially with axons of lower motor neurons.The transport mechanism of motor neurons has been implicated by some scientists, but other have different ideas.
> Cell Death … is now a prime goal for researchers trying to design effective treatments for ALS
Seriously how can someone write such a sentence? If motor neurons die, then in 2021 state of art with no regeneration in sight, it’s the end of the game. There would be no possibility to revive them.But we know that in ALS motor neurons (and other nervous cells) activate several mechanisms to cope with cellular stress. Those mechanisms like UPR (unfolded protein response) effectively stop the cell, and put it in a kind of “freezed” state in order to protect it from some cellular stress, and if the cellular stress diminishes then the cell starts working again. Scientists are not able to have a common ground about if ALS is a disease of upper motor neurons, other neuronal cells (their importance was neglected until the last 10 years, even though they are much more numerous than neurons) or lower motor neurons. Some scientists even think that ALS starts at the neuromuscular junction (extreme axonopathy). There are even neurodegenerative diseases that starts in muscle (virus that use the enterograde transport mechanism). Other scientists like Braak think this kind of disease starts in guts.
> changes in the mitochondria can be detected before one can find a physical change.
Again a weird statement. It’s trendy to point to “mitochondria” for a lot of chronic diseases, but mitochondria are minuscule, highly dynamics structures that can multiply when there is a need (for example exercise) and be recycled when there is no need. They also move a lot.
Beside mitochondria are minuscule structures that can’t be seen with an ordinary microscope, there are thousands of them in a single cell.
At least in humans, no changes can be detected in mitochondria’s number or localization before symptoms appears, because it would involve making dozen of biopsies of motor neurons on a healthy, and nobody do that even for research. And what would be the medical value of such sample?> glutamate as a destructive factor in ALS
Glutamate is indispensable for our nervous system. More accurately excitotoxicity is thought to be involved in ALS since one hundred year, because most theories about ALS’ etiology are influenced by stroke mechanisms. When glutamate is not recycled correctly at the nervous junction then calcium enters and excess calcium kill cells. But on ALS scientific literature you can find many articles that prove AND many other that disprove this hypothesis. And there are thousand of other similar hypotheses about ALS etiology, the reality is that no one knows.> There is increasing evidence that neuroinflammation accompanies the death of motor neurons in ALS.
Inflamation is a weasel word, it is not specific, neither the word “accompanies”. Like “mitochondria” it’s a magic word which is thrown in conversation when we have no clues about a disease. To be more specific we would have to talk about our various immune systems (innate, adaptive, complement) and their signaling mechanisms like cytokines.
There are scientists like Dr Appel who think that some parts of the immune systems are involved in ALS. These scientists generally tell that the Blood-Brain barrier let the immune system invade the CNS. But the BBB is also some magic word, as actually it’s just a layer of cells around each axon of the lower motor neurons or around the blood vessels in the brain. It’s not (as people commonly imagine) some kind of membrane. So far this has not translated in successful clinical trials. Other scientists have their own pet theories, nobody knows what is correct.In conclusion:
Unfortunately scientists have no clues about ALS and for other neurodegenerative diseases like Alzheimer or Parkinson or some dementia. I think they look at the wrong place.
In the 1990 there was a new generation of young researchers who where attracted by molecular biology. Yet this area of research had been remarkably sterile in general in the last 30 years.If you look at which drugs where used in the 750+ clinical trails, there is no common theme, the drugs used are extremely different and it is rare that the principal investigators write about their mechanism of action. Often the same drug is repetitively tried (like Memantine) even when it failed several times previously. It’s a waste of resources.
What we need are medical doctors who think about healing ALS people, we do not need academics who just want to publish quick and dirty papers full of academic verbiage because that’s the way they get a good career.
Looking after molecular events in motor neurons is not the smartest thing we did in ALS.
-
Hi,
I wrote a book on ALS research in 2019 and I tried to update it every few months.
My last update was in March, after the Arimoclomol fiasco.
I waited to have more results, wrote to Amylyx, but did not receive any other information than what the press had.The title of my book is “Status of Amyotrophic Lateral Sclerosis Research: From stopping the disease to restoring the motor function.”
You can find it on Amazon ($19) and a few other places.I’m not sure most of the research on ALS is really relevant. Other than a few really smart guys like JP Julien or Brian Kaspar, I think there are really few scientists who really think hard about the problem. Most molecular biologists look to me like middle-aged scholars who discussed at length how many angels can stand on the end of a pin. There are nearly no research on muscle wasting.
My personal opinion (which unfortunately changes every week) is that the best option for pALS is to put a lot of attention on how much and what you eat. A pALS needs more calories than the same person when they were healthy, and indeed eating is something much more complicated when you become a pALS.
It used to have a calorie calculator at Kentuky university but it does not work anymore. Harvard did develop a ALS calorie calculator apps for Android and Apple.
I also developed an ALS calorie calculator with the same assumptions (the work of Dr Kasarskis). It’s available on my web site padiracinnovation.orgA very concise version is: Stay at a BMI of 27 with healthy food.
-
> BIIB078 rather than BIIB077.
David, you probably mean BIIB078 rather than BIIB067.
Biogen has 4 therapies:
– BIIB067 (tofersen), the one that Amanda had in mind.
– BIIB078 (IONIS-C9Rx), the one you are discussing David.
– BIIB100 (XPO1 inhibitor), one which may be used against TDP-43 proteopathies, so probably it will be useful to most pALS.
– BIIB105 (ATXN2 ASO) a mediator of TDP-43, so again a therapy that could help most pALS.
TDP-43 therapies could be also useful in subsets of Alzheimer and Parkinson diseases. -
> I believe, correct me if im wrong, that after the treatments you will be eligible for ongoing treatments of toferson regardless if you received the placebo or not
Amanda, you mention “TofersEn” also known as IONIS-SOD1Rx and BIIB067.
Which is for SOD1 mutation, I think that you have that mutation in your family.David discuss of BIIB078 which is for C9orf72 dipeptide repeats.
While both BIIB078 and BIIB067 are developed in a collaboration between Biogen and Ionis Pharmaceuticals, they are two different, non interchangeable therapies.
-
> Biomarkers as neurofilaments and MRI for positive ALS testing should replace the current diagnostics by exclusion.
I agree with MRI of the motor area, because there is a specific signal showing iron surcharge in this area.
But there are pALS that do not display this signal, and neurofilaments are found in most neurodegenerative diseases.I agree that making a diagnostic by exclusion is just a comfortable way for the neuros to say “I do not know what you have, please do not come back”.
-
Recently it was announced that Ropinorole, a Parkinson drug, had some effects in ALS, but there was no accompanying scientific report.
Parkinson’s disease, is caused by a loss of dopamine-secreting neurons in an area of the midbrain called the substantia nigra. Yet it would be a bit strange if there was a common causal mechanism between Parkinson and ALS.
-
Thanks for the kind words!
This article is very interesting.
In my book there is two small parts toward the end, where I discuss of:
* Stopping the disease. That’s where I describe a possible TDP-43 genetic therapy, and it is state of art science. I discussed about it with a prominent ALS French scientist from the team who won the $1M from Prize4Life. Now I think this goal can be achieved in a better manner with peptides or PROTACs. Above I told of Promis Neuroscience, but JP Julien’s team has developed an antibody against dysfunctional TDP-43. Other companies are looking at intrabodies (like in my book’s proposal). A team in Case Western University (Gao and al) has developed a TDP-43 therapy with CPPs, but I do not think they intend to make efforts to commercialize it. That’s a shame, because it is a very simple therapy that would work for most pALS.* Healing from the disease. There I described efforts to replace neurons in vivo. Contrary at one may think, there are scientists with that goal and even some encouraging results. To quickly summarize it, they use variations on the Yamanaka’s factors to either heal neurons and make them sprout new axons or to replace a died neuron with a new motor neuron derived from some close cell type, like the astrocyte. In this last case a new axon as still to be grown, as astrocytes have only normal, short dendrites. For example, Check that, it’s mind blowing.
-
I just want to add that the defunct ALS Prize4Life organization arrived at the same conclusion a few years ago.
-
I’m presuming you are taking active steps in promoting your idea so that a cure can be found.
I try to do my best.
I wrote a book about the state of ALS research, and have exchanged by email with many scientists. Every week or so since 3 years I report on neurodegenerative diseases on my web site.
I have also asked for funding (without success) for a TDP-43 genetic therapy (TDP-43 dysfunction is not specific to motor neurons).
On another ALS forum I discussed about the possibility of an TDP-43 therapy based on Cell Penetrating Peptides as a low cost alternative to a genetic therapy. I know because I exchanged with them, that several scientists and biotechs are interested in research area. For example Promis Neuroscience has PI for a TDP-43 intrabody. Other scientists are looking at PROTACs to achieve a similar goal.
You know there is no lack of research on ALS, every year thousands scientific articles and patents are published. More than 700 clinical trials have been conducted on ALS. However as you know, all these gigantic efforts produce nearly nothing. If we don’t ask if scientists are looking at the right place with the right tools, the same situation will continue for decades. For information in Alzheimer disease, they did more than 2500 clinical trials and still have no clues about a treatment.
This is madness and it shows that if we do not make something strong in the case of ALS, scientists will continue to produce arcane articles, will continue to patent and do unsuccessful clinical trials until the end of time.
We need to talk to black swans in the ALS scientific world, there are some interesting people over there, so hope is not lost.
-
I applaud at every initiative to change the current situation, but my opinion is that ALS research does not need more “awareness” from the general public, nor more funding.
What ALS research needs is to change entirely of paradigm, and that’s not going to happen anytime soon.
As long as ALS research is done exclusively on neurons (it’s only recently that it looked at other nervous cells) it will fail at finding a cure for ALS.
And it’s not simply a question of looking at astrocytes or other macroglia cells types, it is of the utmost importance to look at muscles cells.
Most ALS scientists are molecular biologists that are not interested at all in physiology.If it was a disease exclusively of motor neurons as we are told by most (not all) scientists, why should it start locally then progress? Why would sensory neurons, which share most of the nervous tracts with motor neurons, not be impacted?
ALS organizations should fund only scientists that work either on “ALS as a distal axonopathy” or “ALS as Dying-back axonopathy” which both are neglected ALS research domains.
-
I applaud at every initiative to change the current situation, but my opinion is that ALS research does not need more “awareness” from the general public, nor more funding.
What ALS research needs is to change entirely of paradigm, and that’s not going to happen anytime soon.
As long as ALS research is done exclusively on neurons (it’s only recently that it looked at other nervous cells) it will fail at finding a cure for ALS.
And it’s not simply a question of looking at astrocytes or other macroglia cells types, it is of the utmost importance to look at muscles cells.
This disease is first about muscles.If it was a disease exclusively of motor neurons as we are told by most (not all) scientists, why should it starts locally then progresses? Why would sensory neurons, which share most of the nervous tracts with motor neurons, not be impacted? Most ALS scientists are molecular biologists that are not interested at all in physiology.
ALS organizations should fund only scientists that work either on “ALS as a distal axonopathy” or “ALS as Dying-back axonopathy” which both are neglected research domains.
-
Thanks for the link you gave, but it is a temporary file.
It can be downloaded again here -
I agree with you Steve, it’s not the same thing.
Do you have more information about what to understand with this text:
FDA Orphan Approval Status: Not FDA Approved for Orphan Indication
Thanks!
-
Marion,
A Orphan Drug Designation only means someone has asked FDA to examine the commercial preparedness of a drug.
Anybody can ask this to the FDA (try it)It was indeed examined, but it was rejected. It is written in the link you posted.
Now, there is a lot of misunderstanding here. The FDA will not give an authorization market to a drug simply because someone has filled in a form on Internet. To have some odd of success, an organization needs to prove to the FDA it can spend $20M on clinical trials and that they have at least several dozen MD/PhDs in their staff to back up their claims. It does not work the other way round.
There are many ongoing scientific work on ALS drugs and that have public information about them.
You can look at JP Julien’s team for serious studies on how to stop ALS. Brian Kaspar (the designer of Zolgensma) is even working on therapies to replace motor neurons! So is Xiang-Dong Fu, in the team of Don Cleveland.
Several companies (including Promis Neuroscience) have designed TDP-43 antibodies and even nanobodies. Other teams have designed CPPs or PROTACs against TDP-43.And if there is a thing that makes me sure one ALS drug will soon get market authorization, it is that TDP-43 aggregates are found also in Alzheimer disease. Alzheimer is not a rare disease.
-
Thanks for the link.
In the previous message you wrote:
as I believe they have just been granted Orphan Drug status
Do you agree that this link shows it is NOT approved for Orphan status?
FDA Orphan Approval Status: Not FDA Approved for Orphan Indication
-
In 2021 the European drug agency granted Orphan status to Ganglioside GM1 for treatment of ALS. It was presented by 3R Pharma Consulting GmbH, a consultancy organization which represent probably another organization.
As far I know there was no clinical trial about Ganglioside GM1.
-
> as I believe they have just been granted Orphan Drug status
@Marlon+Ness, I just checked the 2020 and 2021 pages of FDA Orphan drug status, and I can’t find any drug which was granted Orphan status for ALS for those two years. But that does not mean anything, for example Spinogenix claims it had been given this status for ALS this year, yet it can’t be found on FDA’s web sitePlease kindly can you give a pointer to a FDA web page?
-
I agree with Jon, but also with Tomasz Boki. Clearly the communication of the RCH4 team could improve.
However I agree that does not mean that RCH4 is not without interest.
I have two remarks:
– Why should we expect that this RCH4 discovery could not be made by another group/ For example look at: doi.org/10.1212/NXI.0000000000000937In conclusion, we observed a decline in TDP-43 reactivity in patients with ALS. The apparent decrease in levels of high-affinity/avidity anti–TDP-43 NAbs correlates with and thereby predicts disease severity. The decline in high-affinity anti–TDP-43 NAbs might impair the capacity to block and neutralize toxic proteins, and although this requires further investigations, data from this study provide rationale for immunotherapy against aggregated TDP-43 as a promising strategy to slow progression of sporadic ALS.
Several companies are working in this area, for example Promis Neuroscience, IMStar, AC immune.
JP Julien (Imstar CTO) had patented (US10202443B2) such antibodies in 2014, well before RCH4 appeared on ALS forums. They didn’t were able to setup clinical trials, probably because clinical trials need a lot of resources out of reach of a small biotech.– What will happen to the pALS who receive RCH4 when the charity will have no funds?
-
There are ~120 genes with mutations related to ALS in ALSSoD database.
But 3 genes are very common: C9orf72, which is found in half of familial cases, SOD1 in one out of 5 familial cases and FUS gene mutations.Each of those genes are pathogenic only if the bear mutations, for example SOD1 normally protects us from oxidative stress, but some mutations make it less efficient. For each gene there are dozen mutations, sometimes hundreds, each corresponding to a different disease phenotype. For example some pALS with some SOD1 mutations can live up to 20 years after diagnostic, which is often equating to a normal life span. Some other SOD1 mutations are associated with very short life.
But ALS genes are certainly not the main cause of ALS, as otherwise it would strike very early in life, like in SMA, a motor neuron disease that strikes toddlers, which is due to a mutation in SMN1 gene.
-
“Neurons cells are close cousins to muscle cells…”
Motor Neurons that die are not as replaceable as muscle cells.
That was true until a few years ago.
But since 2017 at least, scientists are working in replacing motor neurons. Those scientists do not work in the ALS field, they work in the field of regenerative medicine. It’s a pity that ALS organizations do not fund heavily this field of medicine.
This is even known form prominent ALS researchers. For example in June 2019 Don Cleveland suggested during a conference,
that instead of inhibiting this or that ALS protein, ASOs could
give rise to brand new neurons in a sick or aging brain. This is extremely important for pALS!This kind of research has already succeeded in reversing Parkinson’s disease in mice!