The urea cycle is the major pathway for detoxification of ammonia in mammals. Arginase I deficiency is thought to be the least common of the urea cycle disorders and results in hyperargininemia. In humans, deficiency of this enzyme is characterized clinically by progressive mental impairment, spasticity, growth retardation, and periodic episodes of hyperammonemia. This proposal is two-fold: 1) to develop gene-based correction of arginase deficiency with viral vectors and to closely examine corrected animals behaviorally and biochemically;and 2) to evaluate the role elevated arginine and related metabolites (beyond just ammonia) have on the developing brain and development of mental retardation in arginase deficiency. Preliminary data: Our research group has: 1) constructed and characterized the arginase I knockout mouse;2) demonstrated at least short-term (if not longer) correction and rescue with recombinant helper-dependent adenoviral vectors and adeno-associated viral vectors;3) demonstrated that knockout mouse neurons have a higher percentage of cells in the S phase of the cell cycle;4) shown that differentiated neurons from knockout mice have a more mature morphology;and 5) shown that knockout neurons demonstrate induction of genes related to protection from oxidative damage.
In Aim 1, recombinant viral vectors will be used to rescue mice from lethality and to obtain a better understanding of the challenges facing neonatal gene therapy that involve rapid cellular proliferation and potential loss with episomal vs. integrated vectors.
In Aim 2, the effect of hyperargininemia on the nervous system will be examined in vitro along with GABA and glutamine synthesis/release, and extensive microarray analysis.
In Aim 3, the effect of hyperargininemia on the nervous system will be examined in vivo along with GABA and glutamine synthesis/release, guanidino compound determination, and the role that nitric oxide and its metabolites may have on nervous system injury. Successful completion of the proposed studies will provide a molecular understanding of the mechanism of injury to the brain in arginase I deficiency and related disorders. In addition, it is expected that a gene replacement strategy will have been developed for arginase deficiency through these studies and that the information obtained in treating neonates that have developing tissues undergoing rapid proliferation will be applicable to other inborn errors of metabolism.

Public Health Relevance

This project will further elucidate the role arginase plays in health and the mechanisms of disease and neurological insult in its deficiency. In addition, it will be directed at developing a gene replacement strategy for this disorder. Neonatal gene therapy has particular challenges related to rapid cellular proliferation and this proposal will examine gene therapy in that context with application to how such strategies can cure other similar diseases that afflict newborns.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Mavila, Nirmala; Trecartin, Andrew; Spurrier, Ryan et al. (2017) Functional Human and Murine Tissue-Engineered Liver Is Generated from Adult Stem/Progenitor Cells. Stem Cells Transl Med 6:238-248
Cantero, Gloria; Liu, Xiao-Bo; Mervis, Ronald F et al. (2016) Rescue of the Functional Alterations of Motor Cortical Circuits in Arginase Deficiency by Neonatal Gene Therapy. J Neurosci 36:6680-90
Tai, Denise S; Hu, Chuhong; Kim, Elizabeth H et al. (2015) Augmentation of transgene-encoded protein after neonatal injection of adeno-associated virus improves hepatic copy number without immune responses. Pediatr Res 78:239-246
Hu, C; Tai, D S; Park, H et al. (2015) Minimal ureagenesis is necessary for survival in the murine model of hyperargininemia treated by AAV-based gene therapy. Gene Ther 22:111-5
Tai, D S; Hu, C; Lee, C C I et al. (2015) Development of operational immunologic tolerance with neonatal gene transfer in nonhuman primates: preliminary studies. Gene Ther 22:923-30
Hu, Chuhong; Kasten, Jennifer; Park, Hana et al. (2014) Myocyte-mediated arginase expression controls hyperargininemia but not hyperammonemia in arginase-deficient mice. Mol Ther 22:1792-802
Awe, Jason P; Lee, Patrick C; Ramathal, Cyril et al. (2013) Generation and characterization of transgene-free human induced pluripotent stem cells and conversion to putative clinical-grade status. Stem Cell Res Ther 4:87
Kasten, Jennifer; Hu, Chuhong; Bhargava, Ragini et al. (2013) Lethal phenotype in conditional late-onset arginase 1 deficiency in the mouse. Mol Genet Metab 110:222-30
Lee, E K; Hu, C; Bhargava, R et al. (2013) AAV-based gene therapy prevents neuropathology and results in normal cognitive development in the hyperargininemic mouse. Gene Ther 20:785-96
Lee, Eun K; Hu, Chuhong; Bhargava, Ragini et al. (2012) Long-term survival of the juvenile lethal arginase-deficient mouse with AAV gene therapy. Mol Ther 20:1844-51

Showing the most recent 10 out of 12 publications