Gene Therapy for Inborn Errors of Hepatocyte Metabolism

Inborn errors of liver metabolism are frequent causes of morbidity and mortality. For several of these diseases, treatment approaches depend on the manipulation of the metabolic pathway by diet, drugs, vitamin cofactors, enzyme induction, end-product replacement, and alternative pathway activation. Unfortunately, these approaches often remain unsatisfactory especially in the face of illness or catabolism. Some of these disorders require organ transplantation which is an invasive procedure with significant risks. Ideally, transfer of the genes which is deficient in inborn errors of metabolism to the liver cells might restore the metabolic function and provide long-term cure for several of these disorders. The goal of our project is to design and test gene-based therapeutic strategies to correct inborn errors of liver metabolism which are potentially applicable to literally hundreds of metabolic diseases of the liver. We focused our attention on primary hyperoxaluria type 1 (PH1) as a disease model. PH1 is a good disease candidate for gene therapy because of a favorable risk-benefit ratio, availability of direct measures of clinical benefit, and sufficient number of patient available for enrollment in a clinical trial. Therefore, a major goal of this proposal is to generate proof-of-principle studies in the PH1 mouse model using a gene-based approach for liver-directed gene therapy of PH1.