Cell and Gene Replacement Strategies for Arginase Deficiency

精氨酸酶缺乏症的细胞和基因替代策略

基本信息

批准号：
10115139
负责人：
Gerald S Lipshutz
金额：
$ 32.87万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115139
关键词：
ARG2 gene Address Adolescent Affect Age Ammonia Animals Arginine Behavior Behavioral Biochemical Birth Cell Therapy Cells Clinical Congenital neurologic anomalies Cytokinesis DNA Sequence Alteration Data Development Differentiated Gene Disease Drug Metabolic Detoxication Encapsulated Enzymes Extrahepatic Gene Expression Gene Transduction Agent Genes Goals Grant Growth Growth Factor Hepatic Hepatocyte Human Hydrogels Hyperammonemia Hyperargininemia Immune response Impairment Infiltration Injectable Investigation Kidney Knockout Mice Lead Learning Life Liver Longevity Mammals Mediating Metabolism Methods Mus Muscle Muscle Cells Nanotechnology Neonatal Nervous System Trauma Neurons Newborn Infant Nitrogen Pathway interactions Patients Periodicity Peripheral Phenotype Plasma Primary carcinoma of the liver cells Production Prostate Protein Isoforms Psyche structure Recombinants Research Risk Site Stem cell transplant Technology Testing Time Tissue Engineering Tissues Urea Urea cycle disorders Viral Vector adeno-associated viral vector arginase base behavior test clinical application effective therapy enzyme deficiency experimental study gene correction gene replacement gene therapy genome editing improved induced pluripotent stem cell knockout animal liver cell proliferation mouse model muscle form nanoencapsulated novel strategies novel therapeutics null mutation promoter scaffold spasticity stem cell engraftment stem cells urea cycle viral genomics

项目摘要

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.

项目摘要/摘要尿素周期是哺乳动物中氨解毒的主要途径。精氨酸酶1缺乏是尿素周期疾病中最不常见的，并且导致高氨基蛋白血症。在人类中，缺乏该酶在临床上以进行性心理障碍，痉挛，增长智慧和高症血症的周期性发作。该提议是两个方面：1）继续推进基于基因的使用适当的鼠模型的精氨酸酶缺乏症的疗法；病毒载体和基因组校正技术将应用于检查动物是否可以在行为和生化上纠正；和2）到用放置在生物活性支架上的肝细胞评估IPSC衍生的细胞疗法，以提供尿素周期功能。初步数据：我们的研究小组（除其他发现）：1）构建和表征精氨酸酶1基因敲除鼠标； 2）表现出长期生存和重组的生存和救援腺相关病毒载体； 3）证明长期仅需要低级尿素。生存； 4）表明，使用一系列治疗精氨酸酶敲除动物的行为测试缺乏神经系统异常，与同窝姐妹相比，学习或行为没有差异； 5）显示外周代谢可以控制循环血浆精氨酸。 6）精氨酸酶基因的丧失表达导致内在兴奋性异常和神经元的树突状乔木。在AIM 1中，长期将通过病毒载体基因疗法表达精氨酸酶2在肌肉中的表达，以检查生化和精氨酸酶缺乏模型中的表型校正。这种方法可能避免中和免疫无效突变患者的反应。在AIM 2中，研究将检查是否在脚手架上生长的辅助肝脏可以提供最小的尿素循环功能，以导致高氨基血症的表型矫正。这对于其他尿素周期疾病，方法可能成功。随着拟议的研究成功完成预计，对于患有折磨的患者，对基因和细胞置换的新疗法将更接近一步。精氨酸酶缺乏。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis.

DOI：
10.1038/s41467-022-32904-x
发表时间：
2022-09-05
期刊：
Nature communications
影响因子：
16.6
作者：
通讯作者：

Immune Responses and Immunosuppressive Strategies for Adeno-Associated Virus-Based Gene Therapy for Treatment of Central Nervous System Disorders: Current Knowledge and Approaches.

DOI：
10.1089/hum.2022.138
发表时间：
2022-12
期刊：
HUMAN GENE THERAPY
影响因子：
4.2
作者：
Prasad, Suyash;Dimmock, David P.;Greenberg, Benjamin;Walia, Jagdeep S.;Sadhu, Chanchal;Tavakkoli, Fatemeh;Lipshutz, Gerald S.
通讯作者：
Lipshutz, Gerald S.