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Adeno-associated viral gene therapy with AAV9-GCDH 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), based on the administration of adeno-associated viruses (AAV9) that express the GCDH gene, in the Gcdh - / - mouse model. Untreated GA-I patients are at high risk of developing neurological damage between the 3-36 months of age, 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. GCDH deficient cells cannot adequately metabolize lysine and as a result there is a high accumulation of the neurotoxic metabolites glutarylcarnitine and glutaric acid. The early exposure of Gcdh - / - mice to this diet, induced the accumulation of metabolites in different tissues and compromised mouse survival in 40% of the animals. We studied the effects of an early intervention of the therapeutic vector AAV9-GCDH, on Gcdh - / - mice exposed to the lysine-rich diet and observed that the injection of the vector to two-day-old mice resulted in the expression of GCDH in brain and liver at 4 weeks of age. Interestingly, the induction of glutarylcarnitine as a result of the high lysine diet, was not observed in treated animals. In addition, all treated mice survived to the diet exposure. In summary, these early studies indicate that the AAV9-GCDH vector, administered in post-natal animals corrects the devastating effects of exposure to a high lysine diet and suggests its therapeutic potential.


Scientific Production
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Communications at international conferences 2


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