AAV9 gene replacement therapy for respiratory insufficiency in very-long chain acyl-CoA dehydrogenase deficiency

UMMS Affiliation

Department of Pediatrics; The Li Weibo Institute for Rare Diseases Research

Publication Date


Document Type



Biochemical Phenomena, Metabolism, and Nutrition | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Enzymes and Coenzymes | Genetic Phenomena | Genetics and Genomics | Therapeutics


Very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an autosomal recessive disorder of fatty acid oxidation. Fatty acids are a major source of energy during catabolic stress, so the absence of VLCAD can result in a metabolic crises and respiratory insufficiency. The etiology of this respiratory insufficiency is unclear. Thus, our aims were: (1) to characterize respiratory pathophysiology in VLCADD mice (VLCAD(-/-) ), and (2) to determine if AAV9-mediated gene therapy improves respiratory function. For the first aim, VLCAD(-/-) and wild-type (WT) mice underwent an exercise/fast "stress protocol" and awake spontaneous breathing was evaluated using whole-body plethysmography (WBP) both at baseline and during a hypercapnic respiratory challenge (FiO2 : 0.21; FiCO2 : 0.07; nitrogen balance). During hypercapnia, VLCAD (-/-) mice had a significantly lower frequency, tidal volume, minute ventilation, and peak inspiratory and expiratory flow, all of which indicate respiratory insufficiency. Histologically, the cardiac and respiratory muscles of stressed VLCAD (-/-) animals had an accumulation of intramyocellular lipids. For the second aim, a single systemic injection of AAV9-VLCAD gene therapy improved this respiratory pathology by normalizing breathing frequency and enhancing peak inspiratory flow. In addition, following gene therapy, there was a moderate reduction of lipid accumulation in the respiratory muscles. Furthermore, VLCAD protein expression was robust in cardiac and respiratory muscle. This was confirmed by immuno-staining with anti-human VLCAD antibody. In summary, stress with exercise and fasting induces respiratory insufficiency in VLCAD(-/-) mice and a single injection with AAV9-VLCAD gene therapy ameliorates breathing.


AAV9 gene therapy, respiratory insufficiency, very long chain acyl-CoA deficiency

DOI of Published Version



J Inherit Metab Dis. 2019 Apr 17. doi: 10.1002/jimd.12101. [Epub ahead of print] Link to article on publisher's site

Journal/Book/Conference Title

Journal of inherited metabolic disease

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Link to Article in PubMed

PubMed ID