The effect of gene therapy on the pathogenesis of amyotrophic lateral sclerosis (ALS)

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating progressive and neurodegenerative disease. In early stages of ALS, there are known pathological changes in the structure of neuromuscular junctions (NMJ); however, all current gene therapies for ALS target the central nervous system. Evidence pointing to a "dying-back" hypothesis, where the disease begins at peripheral sensory neurons and moves to the CNS, suggests that it may instead be beneficial to target peripheral muscles, axons, and NMJs. Microtubules make up an important part of the NMJ cytoskeleton, allowing transport of important molecules and structural stability. In ALS, the microtubules are found to have critical deficits affecting microtubule-dependent transport. To address this issue, we singularly injected Stathmin1 via an AAV9 intracerebroventricular (ICV) injection at P0-P5 in a SOD1G93A ALS mouse model (both males and females). Stathmin1 (Stmn1) is a protein that depolymerizes microtubules in the cytoskeleton to allow the breakdown of "diseased" microtubules to make room for the body to build new, healthy ones. This study was designed to target the degenerative processes of skeletal muscle NMJs in ALS using an AAV9 injection of Stmn1 to upregulate this gene. We examined the effects of this treatment by assessing overall survival, limb function, swallowing function, and respiratory function. By analyzing these parameters, we concluded that the Stmn1 injection does not have a beneficial or detrimental effect on respiratory or swallowing function at the 6 week timepoint, or limb function up to 17 weeks in the SOD1G93A mouse model, but it does have a slight beneficial effect on disease onset and overall survival at the 17 week time point. These results suggest a possible explanation for the mechanisms of ALS and a potential target for treatment.