Combination AAV therapy with galectin-1 and SOD1 downregulation demonstrates superior therapeutic effect in a severe ALS mouse model

Megan C Baird; Shibi B Likhite; Tatyana A Vetter; Joseph R Caporale; Holly B Girard; Florence S Roussel; Abigail E Howard; Maura K Schwartz; Addison R Reed; Abuzar Kaleem; Xiaojin Zhang; Kathrin C Meyer

doi:10.1016/j.omtm.2024.101312

Combination AAV therapy with galectin-1 and SOD1 downregulation demonstrates superior therapeutic effect in a severe ALS mouse model

Mol Ther Methods Clin Dev. 2024 Aug 6;32(3):101312. doi: 10.1016/j.omtm.2024.101312. eCollection 2024 Sep 12.

Authors

Megan C Baird^{1

2}, Shibi B Likhite¹, Tatyana A Vetter^{1

3}, Joseph R Caporale¹, Holly B Girard¹, Florence S Roussel¹, Abigail E Howard¹, Maura K Schwartz^{1

2}, Addison R Reed¹, Abuzar Kaleem¹, Xiaojin Zhang¹, Kathrin C Meyer^{1

2

3}

Affiliations

¹ Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
² Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
³ Department of Pediatrics, The Ohio State University, Columbus, OH 43210, USA.

Abstract

Neuroinflammation is a miscreant in accelerating progression of many neurodegenerative diseases, including amyotrophic lateral sclerosis (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 the pathogenesis of ALS, and multiple studies have shown correction of each cell type has beneficial effects on disease outcome. Previously, we shown that AAV9-mediated superoxide dismutase 1 (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 (Gal1) and combined this with our previously established AAV9.SOD1.short hairpin RNA treatment. We show Gal1 conditioning of SOD1 ^G93A microglia decreases 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.

Keywords: AAV; SOD1G93A mouse; amyotrophic lateral sclerosis; combination therapy; galectin; gene therapy; microglia; motor neuron disease; neuroinflammation; non-cell autonomous toxicity.