Genetics and Treatment of Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is the neurodegenerative disease with the worst prognosis (along with prion disease), with an average life span from diagnosis to death of 2-5 years. Also known as Lou Gehrig's disease in the English-speaking world and Canada, or Charcot disease in the French-speaking world, this motor neuron disease has two prevalent forms:
- bulbar, with speech and swallowing impairment
- which affects mostly the upper and lower limbs, followed by paralysis, respiratory failure and death.
Fifteen percent of ALS cases are familial, with an important genetic component; and the rest are sporadic cases, which apparently manifest for the first time in the family. The most frequent genetic mutations are found in the following genes: C9orf72 (20-50%), SOD1 (10-20%), TARDBP (5%), FUS (5%), OPTN (4%), VCP (2%), DCTN1 (1%) and other genes whose mutations appear with a frequency of less than 1% (MAT3, HNRNPA1, UBQLN2, SQTM1, TBK1, ANG, PFN1, CHCHD10, TUBA4A). Mutations in these genes, together with various external risk factors, are responsible for familial ALS and sporadic ALS, whose pathogenesis is characterized by selective neurodegeneration associated with glutamate excitotoxicity, mitochondrial damage, autophagy, alterations in oxidative metabolism, axonal transport disorder and dysfunction of microglia and astroglia, all of which precipitate a cascade of accelerated neuronal deterioration that ends the patient's life within a few years.
ALS is incurable, but there are two FDA-approved drugs that delay the course of the disease: Riluzole (Rilutek) and Edaravone (Radicava). In view of the scarcity of therapeutic resources, an urgent search for possible treatments has been initiated, reviewing drugs already approved by the health authorities for the treatment of other ailments, in order to see if any of them are useful in ALS. Among these drugs, currently under study, the following stand out: Tauroursodeoxycholic acid, Mexilene, Ezogabine, Dimethyl fumarate, Interleukin-2 (IL-2), Triumeq (Dolutegravir, Abacavir, Lamivudine), Ibudilast (MN-166), Tamoxifen, Memantine, Perampanel, Rasagiline, Masitinib, Methylcobalamin and Arimoclomol. Other alternatives being worked on are stem cell therapy, gene therapy, antisense oligonucleotides and gene editing with CRISP-Cas9 techniques.
References
- Kiernan MC et al. Improving Clinical trial outcomes in amyotrophic lateral sclerosis. Nature Reviews Neurology 2021; 14:104-118.