Treatment of VLCAD deficient patient fibroblasts with peroxisome-proliferator activated receptor δ agonist improves cellular bioenergetics

Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive disease that prevents the body from utilizing long chain fatty acids for energy, most needed during stress and fasting. Symptoms can appear from infancy through childhood and adolescence or early adulthood, and include hypoglycemia, recurrent rhabdomyolysis, myopathy, hepatopathy, and cardiomyopathy. REN001 is a peroxisome proliferator activated receptor delta (PPARδ) agonist that modulates gene expression of fatty acid β-oxidation enzymes and oxidative phosphorylation proteins. VLCADD fibroblasts responded differently to REN001 based on genotype. All cells had statistically significant increases in ACADVL gene expression. Small increases in VLCAD protein and enzyme activity were observed and were cell line and dose dependent. Cellular bioenergetics improved in all REN001 treated fibroblasts as demonstrated by oxygen consumption rate and ATP production. VLCADD fibroblasts containing missense mutations responded better to REN001 treatment than one containing a duplication mutation in ACADVL . REN001 treated VLCADD fibroblasts results in an increase in VLCAD protein, enzyme activity, and a decrease in cellular stress. These results establish REN001 as a potential therapy for VLCADD as enhanced expression may provide therapeutic increase in total VLCAD activity but suggests the need to mutation specific treatment augmented by other treatment measures.