Combination AAV Gene Therapy with Galectin-1 and SOD1 Downregulation Demonstrates Superior Therapeutic Effect in a severe mouse model of ALS

Abstract

Neuroinflammation is a miscreant in accelerating progression of many neurodegenerative diseases, including ALS. However, treatments targeting neuroinflammation alone have led to disappointing results in clinical trials. Both neuronal and non-neuronal cell types have been implicated in pathogenesis of ALS, and multiple studies have shown correction of each cell type has beneficial effect on disease outcome. Previously, we showed that AAV9-mediated SOD1 suppression in motor neurons and astrocytes significantly improves motor function and extends survival in ALS mouse models. Despite neuron and astrocyte correction, ALS mice still succumb to death with microgliosis observed in endpoint tissue. Therefore, we hypothesized that the optimal therapeutic approach will target and simultaneously correct motor neurons, astrocytes, and microglia. Here, we developed a novel approach to indirectly target microglia with Galectin-1 and combined this with our previously established AAV9.SOD1.shRNA treatment. We show Galectin-1 conditioning of SOD1^G93A microglia reduces inflammatory markers and rescues motor neuron death in vitro. When paired with SOD1 downregulation, we found a synergistic effect of combination treatment in vivo and show a significant extension of survival of SOD1^G93A mice over SOD1 suppression alone. These results highlight the importance of targeting inflammatory microglia as a critical component in future therapeutic development.