# Cell and Gene Replacement Strategies for Arginase Deficiency

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $328,903

## Abstract

Project Summary/Abstract
The urea cycle is the major pathway for detoxification of ammonia in mammals. Arginase 1 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 continue to advance gene-based
therapies for arginase deficiency utilizing appropriate murine models; viral vectors and genomic correction
technology will be applied to examine if animals can be corrected behaviorally and biochemically; and 2) to
evaluate an iPSC-derived cell therapy approach with hepatocytes placed on bioactive scaffolds to supply urea
cycle function. Preliminary data: Our research group has (amongst other findings): 1) constructed and
characterized the arginase 1 knockout mouse; 2) demonstrated long-term survival and rescue with recombinant
adeno-associated viral vectors; 3) demonstrated that only low-level ureagenesis is necessary for long-term
survival; 4) shown that, using an array of behavioral tests, that treated arginase knockout animals lack nervous
system abnormalities and there is no difference in learning or behavior when compared to littermates; 5) shown
that peripheral metabolism can result in control of circulating plasma arginine; and 6) loss of arginase gene
expression results in abnormalities of intrinsic excitability and the dendritic arbor of neurons. In Aim 1, long-term
expression of arginase 2 in muscle by viral vector gene therapy will be performed to examine for biochemical and
phenotypic correction in a murine model of arginase deficiency. This approach may avoid neutralizing immune
responses in patients with null mutations. In Aim 2, studies will examine if an auxiliary liver grown on scaffolds
can supply the minimal urea cycle function necessary to lead to phenotypic correction of hyperargininemia. This
approach may be successful for other urea cycle disorders. With successful completion of the proposed studies it
is expected that a new therapy with gene and cell replacement will be one step closer for patients afflicted with
arginase deficiency.

## Key facts

- **NIH application ID:** 9853849
- **Project number:** 5R01NS100979-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Gerald S Lipshutz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $328,903
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853849

## Citation

> US National Institutes of Health, RePORTER application 9853849, Cell and Gene Replacement Strategies for Arginase Deficiency (5R01NS100979-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9853849. Licensed CC0.

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