Gene therapy using an adeno-associated virus (AAV) appears to amend important abnormalities in patients with long chain fatty acid oxidation disorder (LCFAOD), according to an article recently published in Molecular Therapy.

Specific genetic therapy for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, a form of LCFAOD, with AAV resulted in improvement of laboratory test results, evident in the first 2 weeks after initial treatment, as demonstrated in an experimental study conducted by Stone and colleagues.

“Overall, the results from this study further demonstrate proof-of-concept for an AAV-mediated gene therapy to correct key biochemical and phenotypic aspects of VLCAD deficiency,” the authors wrote.

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The researchers divided mice into 3 groups: the control group, a nontreated VLCAD-deficient group, and another group of mice with the disease treated with ACADVL, the gene that encodes for human VLCAD administered with AAV vector constructs. 

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All mice underwent a cold-fast challenge to assess their ability to maintain a normal temperature and glycemic values in such conditions. Only those in the group with VLCAD deficiency that remained untreated could not thermoregulate and maintain euglycemic values, becoming severely ill.

Moreover, blood glucose and long-chain fatty acyl levels exhibited improvement in the VLCAD deficiency group after gene therapy. These promising findings for the specific gene therapy of LCFAODs remained present for up to 8 weeks.  

The researchers further validated the effectiveness of this therapeutic approach by performing western blot analysis to determine the messenger RNA (mRNA) content in liver, cardiac muscle, and skeletal muscle cells, hence confirming VLCAD protein expression in targeted tissues. 

VLCAD is the most common form of LCFAOD; however, it is still a rare hereditary disease. The rate-limiting step of β-oxidation is impaired, generating hypoketotic hypoglycemia and other pathological consequences in liver, cardiac and skeletal muscle that can be fatal without proper management.

“While dietary management with medium-chain triglyceride oils has proven beneficial in preventing some symptoms, the risk of metabolic decompensation remains throughout a patient’s life, particularly during times of increased energy demand,” the authors wrote.


Stone M, Tutto A, Tang Q, et al. AAV-mediated phenotypic correction of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency in mice. Mol Ther. Published online May 2, 2022. doi:10.1016/j.ymthe.2022.04.017