Gene supplementation of CYP27A1 in the liver restores bile acid metabolism in a mouse model of cerebrotendinous xanthomatosis

• DOI: 10.1016/j.omtm.2021.07.002
• Publication Date: 2021-07-21T22:21:31Z
• Authors: Sara Lumbreras; Ana Ricobaraza; Lucia Baila-Rueda; Manuela Gonzalez-...; Lucia Mora-Jimenez; Iker Uriarte; Maria Bunuales; Matias A. Avila; Maria J. Monte; Jose J.G. Marin; Ana Cenarro; Gloria Gonzalez-A...; Ruben Hernandez-A...
• Keywords: Cerebrotendinous Xanthomatosis; CYP27A1

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene, encoding sterol 27-hydroxylase. Disruption of bile acid biosynthesis pathway and accumulation toxic precursors such as cholestanol cause chronic diarrhea, bilateral juvenile cataracts, tissue deposition cholesterol (xanthomas), progressive motor/neuropsychiatric alterations. We have evaluated therapeutic potential adeno-associated virus (AAV) vectors expressing a CTX mouse model. found that vector equipped with strong liver-specific promoter (albumin enhancer fused α1 anti-trypsin promoter) well tolerated shows effect at relatively low doses (1.5 × 1012 viral genomes [vg]/kg), when less than 20% hepatocytes overexpress transgene. This restored metabolism normalized concentration most acids plasma. By contrast, standard treatment (oral chenodeoxycholic [CDCA]), while reducing cholestanol, did not normalize composition plasma resulted supra-physiological levels CDCA its derivatives. At transcriptional level, only was able to avoid induction xenobiotic-induced pathways liver. In conclusion, overexpression fraction using AAV provides full metabolic restoration Cyp27a1−/− mice. These features make gene therapy feasible option for etiological patients.Graphical abstract