Lind LA, et al. Hum Gene Ther 2020.
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by degeneration of motor neurons and muscles, and death is usually a result of impaired respiratory function due to loss of motor neurons that control upper airway muscles and/or the diaphragm. Currently, no cure for ALS exists and treatments to date do not significantly improve respiratory or swallowing function. One cause of ALS is a mutation in the superoxide dismutase-1 (SOD1) gene; thus, reducing expression of the mutated
gene may slow the progression of the disease. Our group has been studying the SOD1<sup>G93A</sup> transgenic mouse model of ALS that develops progressive respiratory deficits and dysphagia. We hypothesize that solely treating the tongue in SOD1 mice will preserve respiratory and swallowing function, and prolong survival. At 6 weeks of age, 11 SOD1<sup>G93A</sup> mice (both sexes) received a single intralingual injection of gene therapy (AAVrh10-miR<sup>SOD1</sup>). Another 29 mice (both sexes) were divided into 2 control groups: 1) 12 SOD1<sup>G93A</sup> mice that received a single intralingual vehicle injection (saline); and 2) 17 non-transgenic littermates. Starting at 13 weeks of age, plethysmography (respiratory parameters) at baseline and in response to hypoxia (11% O<sub>2</sub>) + hypercapnia (7% CO<sub>2</sub>) were recorded and videofluoroscopic swallow study (VFSS) testing were performed twice monthly until disease end-stage. Minute ventilation during hypoxia + hypercapnia and mean inspiratory flow at baseline were significantly reduced (p<0.05) in vehicle-injected, but not AAVrh10-miR<sup>SOD1</sup>-injected SOD1<sup>G93A</sup> mice as compared to wild-type mice. In contrast, swallowing function was unchanged by AAVrh10-miR<sup>SOD1</sup> treatment (p>0.05). AAVrh10-miR<sup>SOD1</sup> injections also significantly extended survival in females by ~1 week. In conclusion, this study indicates that intralingual AAVrh10-miR<sup>SOD1</sup> treatment preserved respiratory (but not swallowing) function potentially via increasing upper airway patency, and is worthy of further exploration as a possible therapy to preserve respiratory capacity in ALS patients.