Development of Molecular Therapy for Carbamoyl Phosphate Synthetase Deficiency

University Of California Los Angeles, Los Angeles CA

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Abstract

? DESCRIPTION: The urea cycle is the major pathway for detoxification of ammonia in mammals. Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a devastating condition. In humans, deficiency of this enzyme is characterized clinically by periodic episodes of hyperammonemia resulting in progressive mental impairment and a high likelihood of death. This proposal is to characterize a new animal model of the disorder and develop methods for gene-based correction of carbamoyl phosphate synthetase deficiency with viral vectors. Preliminary data: Our research group has: 1) been developing a conditional CPS1-deficient knockout mouse; and 2) demonstrated short-term and long-term expression of transgenes from both recombinant helper-dependent adenoviral vectors and adeno-associated viral vectors after neonatal administration in animals with disorders of intracellular and secreted proteins of the liver resulting in genetic correction (hemophilia A and arginase deficiency). In Aim 1, we will characterize a novel conditional knockout mouse model of carbamoyl phosphate synthetase I deficiency that will be useful for developing therapies for this disorder; and in Aim 2, we will develop novel gene therapy vectors as gene replacement strategies for CPS1 deficiency. These studies will provide important new tools to develop methods for gene correction of CPS1 deficiency and provide a small animal model to study the mechanism of brain injury beyond that of hyperammonemia in proximal urea cycle disorders.