Gene therapy for Cerebrotendinous Xanthomatosis

Resumen

Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene, which encodes a cytochrome implicated in bile acid (BA) synthesis from cholesterol in the liver. The deficiency of this protein produces a metabolic alteration affecting the whole organism. The blockade of the BA synthesis pathway causes accumulation of endogenous neurotoxic intermediates that lead to movement and balance dysfunction, mental retardation and complex psychiatric manifestations, apart from juvenile cataracts and macroscopic deposits of lipids (xanthomas) in different tissues. Among these substances, cholestanol and 7α-hydroxy-4colesten-3-one (7αC4) stand out, although it is suspected that there are other less characterized metabolites that may also contribute. The failure in the synthesis of BAs produces gastrointestinal manifestations due to the malabsorption of nutrients. The conventional treatment of CTX consists of the oral administration of chenodeoxycholic acid (CDCA), which restores intestinal absorption and reduces levels of cholestanol. However, in many patients the neurological manifestations persist and even progress. The main objective of this work is to evaluate whether the transfer of the CYP27A1 gene to the liver using gene therapy techniques is capable of restoring liver metabolism in a Cyp27a1 knock-out mouse model. To this aim, a vector derived from adeno-associated viruses (AAV) has been used. Our results show that a moderate intravenous dose of AAV8-EAAT-CYP27A1 which is an AAV8 vector expressing CYP27A1 under the control of a strong liver-specific promoter (alpha-1 anti-trypsin promoter linked to the albumin enhancer) is able to normalize the levels of CDCA, cholestanol and 7αC4. The impact on neurological function could not be evaluated because the current animal model does present a suitable phenotype. Unlike the standard treatment based on oral CDCA, AAV8-EAAT-CYP27A1 avoids the secondary activation of enzymes involved in xenobiotic responses such as Cyp3a11. In conclusion, gene therapy emerges as a feasible alternative for the treatment of CTX.