Glutaric aciduria type I (GA-I) is a rare metabolic inherited disorder in the catabolic pathways of lysine, hydroxylysine and tryptophan. It is caused by the deficiency of glutaryl-CoA dehydrogenase (GCDH). The enzymatic defect results in the accumulation of glutaric acid, 3-hydroxy glutaric acid and glutarylcarnitine in tissues and body fluids. Clinically, GA-I patients display macrocephaly, progressive dystonia and dyskinesia. Dietary lysine restriction, carnitine supplementation and intensified emergency treatment during catabolism are effective for some individuals. Unfortunately, one-third of affected children do not respond to therapy and experience irreversible brain damage.

We have explored the feasibility of in vivo gene therapy in the preclinical model of the disease, the Gcdh -/- mice, following an intravascular delivery of AAV-GCDH in adult and newborn mice. Adult administration resulted in the restoration of GCDH expression and enzyme activity in peripheral tissues, specillay in liver, but very mildly in brain. Application of the therapeutic vector to newborn mice restored GCDH expression in brain that was maintained for at least six months after treatment. Interestingly, when mice were exposed to a lysine overload to enhance the severity of the disease, AAV-GCDH treatment improved the phenotype by reducing the content of toxic metabolites in brain and ameliorating the neuropathologic damage. Moreover, whereas 50% of untreated Gcdh -/- mice succumbed to a high lysine diet, AAV-GCDH therapy restored survival in 100% of mice. In summary, these data suggest that AAV-mediated gene therapy can prevent from the devastating consequences of GA-I.