Therapeutic tools for familial ALS

Familial ALS (FALS) accounts for 10 to 15% of ALS cases. In more than 70% of FALS patients, a causal gene is identified and animal models have been developed for a subset of them, mainly for the most frequently mutated genes. Therapeutic tools to treat those patients are dominated by gene-specific therapy and the most advanced approaches target the SOD1 gene mutations. Either by direct delivery of antisense oligonucleotides (ASO) or using viral vectors such as adenoviruses (AAV) to deliver ASOs, gene specific therapies have shown promising results in animal models. The recent use of subpial injections of AAV9 + anti SOD1 ASO now shows that the disease is completely prevented or stopped in the animal, depending on the moment of injection, e.g., before or after disease onset. However, the use of viral vectors in humans seems to be limited at least by their immunogenicity. Antibody-based therapies are also efficient to treat animal models, but to a lesser extent. Most of the experiments targeted the SOD1 protein in its misfolded conformation. This approach seems better tolerated than the AAV one, an important limit being the choice of the epitope. Unexpectedly, some advances in treating the C9ORF72 animal model have been obtained using a modulation of microbiota, and this strategy has the great advantage to have an easy route of administration and a good safety profile. The landscape of experimental FALS treatment is rapidly evolving and results are promising. This is an important unmet need for ALS patients and several human phase I, II and III trials are ongoing.(c) 2022 Published by Elsevier Masson SAS.

Automated summary

Familial ALS (FALS) accounts for 10 to 15% of ALS cases. Gene-specific therapy, such as antisense oligonucleotides (ASO) and viral vectors, has shown promising results in animal models, particularly in targeting SOD1 gene mutations. However, the use of viral vectors in humans is limited due to immunogenicity. Antibody-based therapies and modulation of microbiota have also shown potential in treating FALS. The landscape of experimental FALS treatment is rapidly evolving, and human clinical trials are ongoing.