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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<jats:sup>\u2212\/\u2212<\/jats:sup>), and (2) to determine if AAV9\u2010mediated gene therapy improves respiratory function. For the first aim, VLCAD<jats:sup>\u2212\/\u2212<\/jats:sup> and wild\u2010type (WT) mice underwent an exercise\/fast \u201cstress protocol\u201d and awake spontaneous breathing was evaluated using whole\u2010body plethysmography (WBP) both at baseline and during a hypercapnic respiratory challenge (FiO<jats:sub>2<\/jats:sub>: 0.21; FiCO<jats:sub>2<\/jats:sub>: 0.07; nitrogen balance). During hypercapnia, VLCAD<jats:sup>\n<jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> 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<jats:sup>\n<jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> animals had an accumulation of intramyocellular lipids. For the second aim, a single systemic injection of AAV9\u2010VLCAD 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\u2010staining with anti\u2010human VLCAD antibody. In summary, stress with exercise and fasting induces respiratory insufficiency in VLCAD<jats:sup>\u2212\/\u2212<\/jats:sup> mice and a single injection with AAV9\u2010VLCAD gene therapy ameliorates breathing.<\/jats:p>","DOI":"10.1002\/jimd.12101","type":"journal-article","created":{"date-parts":[[2019,4,17]],"date-time":"2019-04-17T07:04:26Z","timestamp":1555484666000},"page":"870-877","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["AAV9 gene replacement therapy for respiratory insufficiency in very\u2010long chain acyl\u2010CoA dehydrogenase deficiency"],"prefix":"10.1002","volume":"42","author":[{"given":"Marina","family":"Zieger","sequence":"first","affiliation":[{"name":"Department of Pediatrics University of Massachusetts Medical School  Worcester Massachusetts"},{"name":"The Li Weibo Institute for Rare Diseases Research University of Massachusetts Medical School  Worcester 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