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

J Inherit Metab Dis. 2019 Sep;42(5):870-877. doi: 10.1002/jimd.12101. Epub 2019 May 3.


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.

Keywords: AAV9 gene therapy; respiratory insufficiency; very long chain acyl-CoA deficiency.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acyl-CoA Dehydrogenase, Long-Chain / deficiency*
  • Acyl-CoA Dehydrogenase, Long-Chain / genetics
  • Animals
  • Carnitine / blood
  • Congenital Bone Marrow Failure Syndromes / genetics
  • Congenital Bone Marrow Failure Syndromes / therapy*
  • Dependovirus / genetics
  • Female
  • Gene Expression
  • Genetic Therapy*
  • Genetic Vectors
  • Lipid Metabolism
  • Lipid Metabolism, Inborn Errors / genetics
  • Lipid Metabolism, Inborn Errors / therapy*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / therapy*
  • Muscular Diseases / genetics
  • Muscular Diseases / therapy*
  • Respiratory Insufficiency / etiology
  • Respiratory Insufficiency / therapy*
  • Transduction, Genetic


  • Acyl-CoA Dehydrogenase, Long-Chain
  • Carnitine

Supplementary concepts

  • VLCAD deficiency