Gene Targeted Therapies for Neurodegenerative Disorders: Strategies and Implications in ALS and SMA

Advances in technology have provided a better understanding of the genetic basis of neurodegenerative disorders and their underlying molecular pathophysiology. However, treating these disorders with conventional strategies is a major challenge. The approval of gene-targeted therapy for spinal muscular atrophy (SMA) has laid the foundation for developing therapies for other neurodegenerative disorders. Highly personalized gene therapy trials have been reported. As intensive research and efforts to advance gene-targeted therapies continue, this review provides an overview of viral and non-viral vectors and delivery methods, as well as treatment strategies, including gene addition, replacement, editing, silencing, and splice modulation. Gene-targeted approaches and clinical trials for SMA and amyotrophic lateral sclerosis (ALS) have demonstrated success, and additional studies are in progress. The design of efficient clinical trials which facilitate successful translation into clinical practice is of critical importance. Key considerations include the selection of appropriate disease models, understanding the natural history of the disease, and establishing well-defined outcome measures to assess prognosis of the disease and therapeutic efficacy. Finally, the precision of CRISPR-gene editing may facilitate the development of new therapies.