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Gene therapy to correct glutaric aciduria type 1 in Gcdh -1- mice

19th national competition for scientific and technical research

Rare diseases

Senior Researcher : Cristina Fillat Fonts

Research Centre or Institution : Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS). Barcelona.


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.


Scientific Production
Magazine Articles 2
Communications at national conferences 3
Communications at international conferences 4


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