Research projects

This project aims to explore the potential of a gene therapy strategy for glutaric aciduria type I (GA-I). Untreated GA-I patients are at high risk of developing neurological damage, following an encephalopathic crisis, triggered by a catabolic state induced by febrile episodes, vaccine administration or small surgical interventions. In the present project, we have induced conditions of catabolic stress in Gcdh - / - mice through the exposure of animals to a high lysine diet (HLD). GCDH deficient cells cannot adequately metabolize lysine and as a result there is a high accumulation of the neurotoxic metabolites glutarylcarnitine, glutaric acid and 3-hydroxy glutaric acid. The early exposure of Gcdh -/- mice to this diet, induced the accumulation of metabolites in different tissues and compromised mouse survival in 60% of the animals. We studied the effects of the delivery of a therapeutic vector in Gcdh - / - mice exposed to a standard or a HLD. With both strategies we observed GCDH expression in the striatum at 4 weeks of age that last for  at least 6 months. The treatment administration showed protective effects of the therapy. The peak induction of glutarylcarnitine, glutaric acid  and 3-hydroxy glutaric acid as a result of the HLD, was not observed in treated animals one and 6 months after treatment. Histological analysis showed that the striatal damage induced by HLD, with areas of large vacuolation, that increased with number and size after long-exposure, were not present in animals receiving intervention.  In addition, all treated mice survived to the diet exposure. These studies demonstrate that our proposed treatment with genetic therapy provides therapeutic benefits.