1. Intralingual Administration of AAVrh10-miR(SOD1) Improves Respiratory But Not Swallowing Function in a Superoxide Dismutase-1 Mouse Model of Amyotrophic Lateral Sclerosis
- Author
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Nicole L. Nichols, Mai K. ElMallah, Angela L McCall, Christian Mueller, Justin S Dhindsa, Lori A Lind, Olivia E. Stricklin, Katherine A. Johnson, Ellyn M Andel, and Teresa E. Lever
- Subjects
Male ,Pathology ,medicine.medical_specialty ,animal diseases ,Genetic Vectors ,Degeneration (medical) ,Superoxide dismutase ,03 medical and health sciences ,Impaired respiratory function ,Mice ,0302 clinical medicine ,Superoxide Dismutase-1 ,Swallowing ,Tongue ,Genetics ,Medicine ,Animals ,Respiratory system ,Amyotrophic lateral sclerosis ,Molecular Biology ,Research Articles ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,Amyotrophic Lateral Sclerosis ,nutritional and metabolic diseases ,Genetic Therapy ,Dependovirus ,medicine.disease ,nervous system diseases ,Deglutition ,Mice, Inbred C57BL ,Disease Models, Animal ,MicroRNAs ,medicine.anatomical_structure ,Phenotype ,030220 oncology & carcinogenesis ,biology.protein ,Breathing ,Molecular Medicine ,Female ,business ,Respiratory Insufficiency - Abstract
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(G93A) 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 it will prolong survival. At 6 weeks of age, 11 SOD1(G93A) mice (both sexes) received a single intralingual injection of gene therapy (AAVrh10-miR(SOD1)). Another 29 mice (both sexes) were divided into two control groups: (1) 12 SOD1(G93A) 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(2)) + hypercapnia (7% CO(2)) were recorded and videofluoroscopic swallow study testing were performed twice monthly until end-stage disease. Minute ventilation during hypoxia + hypercapnia and mean inspiratory flow at baseline were significantly reduced (p 0.05). AAVrh10-miR(SOD1) injections also significantly extended survival in females by ∼1 week. In conclusion, this study indicates that intralingual AAVrh10-miR(SOD1) treatment preserved respiratory (but not swallowing) function potentially via increasing upper airway patency, and it is worthy of further exploration as a possible therapy to preserve respiratory capacity in ALS patients.
- Published
- 2020