Innovative Gene Therapy Shows Promise in Slowing Motor Decline in ALS Patients

Recent advancements in gene therapy have demonstrated significant potential in decelerating motor function deterioration in models of amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disease. Researchers, primarily from the University of Pennsylvania's Perelman School of Medicine and Children's Hospital of Philadelphia, developed a novel approach targeting the underlying causes of ALS. They used RNA interference (RNAi) to silence a gene associated with TDP-43, a protein that mislocalizes and aggregates in neurons of ALS patients, contributing to neuron death.

In preclinical mouse models, this therapy extended survival by an average of 54%, while also improving muscular strength and reducing inflammation within the brain and spinal cord. The method involved delivering RNAi via Adeno-Associated Virus (AAV) vectors into the cerebrospinal fluid, allowing targeted and sustained gene suppression in critical nervous system areas impacted by ALS.

ALS affects approximately 30,000 Americans, with 5,000 to 6,000 new cases each year. The disease progresses rapidly, with many patients surviving only 2 to 5 years post-diagnosis. Current treatments mainly manage symptoms rather than halting disease progression. Notably, most ALS cases lack a specific genetic cause, but about 97% involve abnormal accumulation of TDP-43 protein, which disrupts normal cellular functions.

Building on previous research that linked reduced levels of Ataxin-2 (ATXN2) to lowered TDP-43 pathology, the team employed RNAi to suppress ATXN2. This approach successfully decreased TDP-43 mislocalization and neuronal death in both murine models and human-derived spinal cord cells, demonstrating high effectiveness in reducing pathogenic protein levels.

The study also shed light on the broader biological mechanisms of ALS, correcting over 450 gene expression anomalies in mouse models and revealing parallels with human disease genetics. While these findings are promising, further research is required before this therapy can be considered for human trials. Experts highlight that this targeted gene silencing approach could revolutionize ALS treatment by addressing its root causes rather than merely alleviating symptoms.

This groundbreaking research underscores the potential of gene therapy to modify disease progression in ALS and opens new avenues for developing treatments that are both effective and durable.