New Treatment Opportunities For Amyotrophic Lateral Sclerosis

Background: Disease with damage to both central motor neuron (CMN) and peripheral motor neuron (PMN), motor neuron disease (BMN) or amyotrophic lateral sclerosis (ALS), belongs to neuromuscular and neurodegenerative diseases (degeneration or "amyotrophy" of motor neurons). The median age of disease onset is 55 years, and the average survival is 2-5 years. The initial symptoms of ALS may be subtle, but the disease spreads inexorably. This progression is not always constant; some patients have weeks or months with little or no loss of function. Epidemiology: The incidence of ALS in the United States is 1.5 to 2.2 per 100 000, but varies significantly by age, sex, and race. Men have a higher incidence of ALS (1.7-2.6 per 100 000) than women (1.1-1.5 per 100 000). More than 90% of ALS cases are sporadic, and in 5-10% it is a hereditary disease. To date, more than 50 genes have been identified in the etiology of ALS. About 60% of hereditary and 10% of sporadic ALS cases are associated with the four most common genes: SOD1, TARDBP, FUS/TLS and C9ORF72. Etiopathogenesis: The etiology of BMN is believed to involve complex interactions of environmental, lifestyle, and genetic factors, but so far only a few convincing risk factors have been established. This multifactorial nature of disease etiology partly explains why, despite intensive research efforts, effective treatments remain elusive and ALS continues to represent an unmet medical need. Clinical presentation: ALS is a fairly heterogeneous disease. In typical cases, pyramidal signs (CMN) are very clear in the legs (weakness, muscle spasticity, hyperreflexia, Babinski may be positive, but often absent), and in the hands there are symptoms of peripheral motor neuron (PMN) involvement (weakness, muscle hypotrophy, fasciculations), hyperreflexia due to simultaneous CMN damage. New treatmet opportunities: Clinical trials have studied many experimental drugs to slow the progression of ALS in animal models with promising results, however, few have been translated into effectiveness in humans with the disease. Discussion: Until recently, only riluzole, a modest disease-modifying drug, was approved by the US FDA. As of August 2024, the FDA has approved seven drugs to slow disease progression and treat ALS and its symptoms: Rilutek (riluzole, oral tablet) (1995); Tiglutik "thickened" riluzole, oral suspension) (2018); Exservan (oral film riluzole) (2019); Nuedexta (dextromethorphan HBr and quinidine sulfate, capsules) (2011); Radicava (edaravone) (2017/i.v., oral formulation/2022); Relyviro (AMX0035) (powder for oral suspension or through feeding tube) (2022); Qalsody (tofersen) (through lumbar puncture) (2023). Riluzole is the first drug approved for ALS (FDA 1995, EMA 2004) and can slow the progression of the disease. It works by reducing the release of glutamate, a neurotransmitter that can cause neurodegeneration. Edaravone (FDA approved 2017, EMA 2019) is an antioxidant that helps reduce oxidative stress, which may slow the progression of ALS in some patients. Tofersen is specific for ALS associated with SOD1 gene mutation, approved by the FDA and EMA in 2003. It acts as an antisense oligonucleotide that reduces the production of toxic proteins associated with this mutation. Conclusion: There is therefore no curative treatment for ALS, but the mentioned therapies seem to moderately slow the progression of the disease/prolong survival or delay death. Furthermore, while disease-modifying drugs have limited benefit, symptomatic treatments have a major impact on survival and quality of life.