There are multiple subtypes of ALS: It could be of genetic origin, for example, an uncommon version of a SOD1, FUS, or C9orf72 genes might under some unknown conditions lead to ALS in aging people. But most people with ALS have no genetic alleles yet they developed ALS, perhaps due to some environmental conditions, like ingesting some toxins. In most cases people with ALS have a biomarker: They have aggregates of a very common protein, TDP-43, which localizes at an unlikely place in the neuron cells.
Some other things that are a bit weird in ALS, if it's of genetic origin why only aged people are striked? Why does it start with a seemingly innocuous muscular problem that soon extends to the whole body, but only for a specific type of muscle? The only therapy up to now, which seems to be a breakthrough is Qalsody, a genetic therapy by Biogen and Ionis. Unfortunately, it aims at a specific variant of the SOD1 gene which is present only in very few ALS patients. SOD1 variants are implicated in only 2% of ALS cases, and there are hundreds of SOD1 variants, while Qalsody targets only one of them.
In 2019 following the arrival of a SMA therapy, I made a plea for a genetic therapy aiming at TDP-43. Many scientists have been working on it in recent years, and it seems that one of those efforts is starting to show some results.
In 2011, Shulin Ju, Gregory A Petsko and colleagues found that hUPF1, a human gene, rescues the toxicity of FUS/TLS in a yeast model of ALS. This does not mean much as indeed there is an abyss between a yeast model of ALS and human beings. Yeasts are very different from mammal cells, but they are cheap so they are convenient for testing a large array of substances. The scientists identified several human genes that, when over-expressed in yeast, can rescue the cell from the toxicity of mislocalized FUS/TLS. This was confirmed again in 2013.
In 2015 the same team progressed pre-clinical trials research by demonstrating that on a rat model of ALS, human UPF1 exerted protective effects. The rat model was based on an over-expression of TDP-43. What was astonishing was that first there was no mortality between rats, second, it would demonstrate action both on FUS repeats and TDP-43 mislocalization which are very different diseases at the molecular level. This was again confirmed in 2015 by the same team while alluding that possible ALS therapy might also be useful for FTD, a type of dementia.
Astonishingly in 2021 another team led by Benjamin L Zaepfel, in the laboratory of well-known ALS scientist Jeffrey D Rothstein, found that UPF1 reduces C9orf72 neurotoxicity in an iPSC model of the disease. This might at the same time look insignificant (an iPSC model) and very significant (a therapy working for FUS/C9orf73/TDP-43).
Some of the scientists involved in this research work in a biotech MeiraGTx. MeiraGTx among other therapies, has designed a gene therapy for amyotrophic lateral sclerosis.
In a presentation on Oct. 27 at the European Society of Cell and Gene Therapy conference in Brussels, MeiraGTx showed that a single treatment with its gene therapy AAV-UPF1 prevented the loss of motor neurons in mouse and rat models with genetic and cellular defects seen in ALS
What is the significance of this? I do not know. UPF1 is a gene that encodes a protein that is part of a post-splicing multiprotein complex, the exon junction complex, involved in both mRNA nuclear export and mRNA surveillance. This has a relation with FUS and C9orf72, but not with TDP-43 versions of the disease.
Any way at least if it works in human patients with FUS/C9orf72 that would mean one in five ALS patients would benefit from it. This would be much larger than Qualsody benefits.
If it works for TDP-43 it would heal most ALS and FTD cases. This would represent a large number of patients, FTD prevalence is 20/100,000 persons.
This presentation was probably a call to investors such as Biogen, to fund clinical studies. Let's hope it works.
In the case of ALS, the clusters of TDP-43 are also located in the cytosol, i.e. where the proteins are produced, before being folded up in the ER and then sent to their place of use by the Golgi apparatus. After shipment, TDP-43 should be in the nucleus.