An half interesting story about two studies.

[Dagmar]

Thank you for posting this Jean-Pierre, at least there is progress (albeit, slow) in identifying how to manipulate errant genes and thus control the toxicity they create.

Could you please go one step further, and explain how this will impact ALS patients? Will this open the door to a new understanding of cause? How long will it take to go from discovery to actual human trials and a successful treatment? Thank you.

[Jean-Pierre Le Rouzic]

Thanks Dagmar,

But do not expect too much from me I am not a doctor or a scientist, only a retired R&D engineer with a strong interest in biology. I will try to do my best to answer those questions. Another caveat: ALS diagnostic is achieved through an exclusion process, and if your neurologist is in hurry, the diagnostic might not be so accurate. My advice to people having a familial form is to take a genetic test for the 10 most common “ALS genes”.

> How this will impact ALS patients?

It will impact only the fraction (8% of all cases) of patients that have a familiar form of ALS. The familial form is said to represent 10% of all cases. In the familiar form (as far I understand it) there are two main sub families:

• SOD1. The first discovered gene that is implicated in familiar ALS. This accounts for roughly 2% of all ALS cases. pALS with SOD1 have lowered resistance to the oxidative stress (which is a part of metabolism). This study is not about SOD1.
• C9orf72. The study is about the 8% of all pALS, that have a mutation in this gene. A gene produces one or several proteins, it’s a quite convoluted process. When there is a mutation in a gene, proteins are altered and diseases happen. In C9orf72 ALS mutations proteins are produced which are toxic for the neuron. Just for the reference they are called dipeptide repeat proteins (DPRs). Poly(GR) is an instance of DPR which is particularly damaging specially to vesicles in cells that are called mitochondria and that are essential to the cell metabolism. The scientists show that reducing the amount of Poly(GR) (also written Poly-GR). A doctor, Ludo Van Den Bosch, said: “It strongly indicates that therapeutic strategies lowering the expression of toxic dipeptide-repeat proteins can reverse disease phenotypes, even after disease onset”. Reversing disease phenotype means that cells that were slowly dying from the toxic proteins have recovered.
• For the pALS that do not have a familial form (90% or more) the cause of ALS is quite clear since a couple of year, it is misfolded proteins. So they are not interested in this study. Misfolded proteins result of a different mechanism than in SOD1 or C9orf72 cases.
  – SOD1 mechanism is a reduced expression of a gene.
  – C9orf72 is a gene that produces toxic proteins.
  – non familial ALS is about mismanagement of proteins after they are produced by the cell’s nucleus. Normally proteins are processed in a complex organ in cell that is named ER, which role is to fold the long filament that was produced by the gene (and RNA and ribosome). Folding a protein is very important because it confers additional functions to the protein. In non familial forms of ALS, misfolded proteins such as TDP-43 or FUS are not processed and aggregate in granules in the cell cytoplasm, which in turn slowly disrupt the cell, and indeed the proteins are missing elsewhere, for example TDP-43 is useful against some viruses.

> Will this open the door to a new understanding of cause?

For C9orf72 related ALS, the cause is clear at least since 2013: Toxic DPRs are produced by the mutated genes.

What is new knowledge is that cells can recover. Indeed when a pALS is diagnosed she/he had lost a significant number of cells that will not recover. But that is an area for treatments like Nurown and its successors.

> How long will it take to go from discovery to actual human trials and a successful treatment?

That is more a question about politics and business that science. And it will need at least 10 years before this research translates in drugs on the market.
When an university scientist finds something that have a business potential they patent it. Healthcare is one of the largest market in many countries, so I am quite sure they will patent their findings.
Then someone has to take an interest to develop the research, sometimes it is the scientist that found something but usually it is not. Often their management do not agree to develop the treatment because in academy is interested only by academic matters and clinical trials are a costly, uncertain and complex project which needs much more resources that any university lab can mobilize. Discovering  is the easy part of the job, creating a safe drug and making doctors prescribe it is much more difficult.
So a biotech pays the patent, sizes the research and invents a safe drug (a hard task), and tries to do a clinical trial. To do so it had to convince investors which is a bit tricky, investors will fund the research only if there is business potential. Then it has to convince authorities that it is serious enough, that they won’t kill patients.
If after 5 years the biotech succeed in the three phases of clinical trials, often their research is bought by a major company such as Novartis, the investors get their money and more, and the major firm has the not so obvious task to “educate” medical doctors about the new treatment, before they accept to prescribe it. Sometimes they need several years to do so. Medical doctors are extremely conservative, they do not want to take risks with a new drug. So major companies have to write articles in professionals journals, make presentations at conferences, organize workshops, discuss with doctors and patients organizations. It costs them billions Dollars.

 

 

[Dagmar]

Wow! What a wonderful explanation. Thank you for taking the time to write that – – I hope our forum members take the time as well to read what you shared.

This not only relates to the studies in your initial post; but provides a good “big picture” explanation of the difference between familial and non-familial ALS, causes of each and the uphill battle (and time) from discovery to treatment – – and then, gaining physician confidence!

Thank you!

[Diana Belland]

I second Dagmar’s thanks to you for your thorough explanation of the process from discovery to treatment.  I found it discouraging to read that it takes “at least 10 years before this research translates in drugs on the market.”   I guess all we can do is “keep on keeping on,” and do the best we can to make the most of each day we have.    I could use a little more of Dagmar’s great positive outlook!   I’m working on it.

Thank you for your many interesting and informative posts!

[Glen North]

Jean-Pierre,

I’m in agreement with everything you said, but must clarify the time it takes a new drug to get to market.  When we’re talking about a drug with marginal but real efficacy,  I believe you are correct in the 10 year range.  Although, for a drug that is discovered to have a profound effect on something like ALS, the clinical trial process would go to probably phase 2, then it would very quickly gain market authorization (my bet would be just over a year).  In order for this to happen the drug would have to of had profound results in a very large percentage of the trial group.

I’m not sure of the probability of that happening any time soon, although the sheer number of players in this space today, the likelihood of it happening is instrumentally greater than even 4 ears ago.  Also I’m sure as with most medical breakthroughs, it will be stumbled upon by accident.  We can always hope that someone quickly stumbles:)

Glen