Treatment of glutaric aciduria type I (GA-I) via intracerebroventricular delivery of GCDH.

ABSTRACT

Glutaric aciduria type I (GA-I) is an autosomal recessive genetic disorder caused by a deficiency in glutaryl-CoA dehydrogenase (GCDH). Patients who do not receive proper treatment may die from acute encephalopathic crisis. Current treatments for GA-I include a low-lysine diet combined with oral supplementation of L-carnitine. A mouse model of Gcdh c.422_428del/c.422_428del (Gcdh -/-) was generated in our laboratory using CRISPR/Cas9. Gcdh -/- mice had significantly higher levels of glutaric acid (GA) in the plasma, liver, and brain than those in wild-type C57BL/6 mice. When given a high-protein diet (HPD) for two days, approximately 60% of Gcdh -/- mice did not survive the metabolic stress. To evaluate whether GCDH gene replacement therapy could be used to provide sustained treatment for patients with GA-1, we prepared a recombinant adeno-associated virus (rAAV) carrying a human GCDH expression cassette and injected it into Gcdh -/- neonates for a proof-of-concept (PoC) study. Our study demonstrated that delivering rAAV to the central nervous system (CNS), but not the peripheral system, significantly increased the survival rate under HPD exposure. Our study also demonstrated that rAAVPHP.eB mediated a higher efficiency than that of rAAV9 in increasing the survival rate. Surviving mice showed dose-dependent GCDH protein expression in the CNS and downregulation of GA levels. Our study demonstrated that AAV-based gene replacement therapy was effective for GA-I treatment and provided a feasible solution for this unmet medical need.