Impact of Intralingual AAVrh10‐miRSOD1 Injection on Respiratory Function in SOD1G93A Mice

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which patients normally succumb to the disease within 5 years of onset. Death is usually a result of impaired respiratory function due to loss of motor neurons that control upper airway muscles and/or the diaphragm. The motor neurons that control upper airway muscles and thereby airway patency are found in the brainstem in a region called the hypoglossal motor nucleus. One cause of ALS is a mutation in the superoxide dismutase‐1 (SOD1) gene that results in the buildup of SOD1 protein in neurons. For this subset of patients, reducing expression of the mutated gene may slow the progression of the disease. The purpose of this study was to determine if delivering a microRNA against SOD1 (miRSOD1) to the hypoglossal motor nucleus of mice that overexpress mutant SOD1 (SOD1G93A) would increase respiratory function. Thus, we hypothesized that intralingual injection of AAV‐miRSOD1 into SOD1G93A mice would knockdown mutant SOD1 in hypoglossal motor neurons and improve respiration. Six‐week‐old male and female mice received intralingual injections of either AAVrh10‐miRSOD1 or vehicle (phosphate buffered saline). Starting at 13 weeks of age, respiratory parameters at baseline and in response to hypoxia (11% O2) + hypercapnia (7% CO2) were studied in miRSOD1‐injected SOD1G93A mice (n=11), vehicle‐injected SOD1G93A mice (n=12), and vehicle injected wild‐type mice (n=17) via whole‐body plethysmography every other week until the SOD1G93A mice reached end‐stage (20% body weight loss). Minute ventilation during hypoxia + hypercapnia and mean inspiratory flow at baseline were significantly reduced (p<0.05) in vehicle‐injected but not miRSOD1‐injected SOD1G93A mice as compared to wild‐type mice. miRSOD1 injections also extended survival in females by ~1 week; although this did not reach statistical significance, we suggest that any increase in survival could be clinically significant. In conclusion, this study indicates that intralingual miRSOD1 treatment restored respiratory function to wild‐type levels (potentially via increasing upper airway patency) and is worthy of further exploration as a possible therapy to preserve respiratory capacity in ALS patients. Future directions include studying the vector genome expression and SOD1 knock down in local and systemic tissues to understand the degree of transduction. In addition, we will measure the impact of intralingual miRSOD1 on swallowing and upper airway function.Support or Funding InformationSupported by NIH R21 NS098131‐02 and K99/R00 HL119606This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.