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.

项目概要/摘要尿素循环是哺乳动物氨解毒的主要途径。精氨酸酶 1 缺乏症被认为是最不常见的尿素循环障碍，并导致高精氨酸血症。在人类中，缺乏这种酶的临床特征是进行性精神障碍、痉挛、生长迟缓和周期性发作的高氨血症。该建议有两个方面：1）继续推进基于基因的研究利用适当的小鼠模型治疗精氨酸酶缺乏症；病毒载体和基因组校正将应用技术来检查动物是否可以在行为和生化方面得到纠正； 2) 至评估 iPSC 衍生细胞治疗方法，将肝细胞放置在生物活性支架上以供应尿素循环功能。初步数据：我们的研究小组（除其他发现外）：1）构建并精氨酸酶 1 敲除小鼠的特征； 2）通过重组证明了长期存活和救援腺相关病毒载体； 3）证明只有低水平的尿素生成对于长期而言是必要的生存； 4）表明，通过一系列行为测试，经过治疗的精氨酸酶敲除动物缺乏紧张感系统异常，与同窝出生的孩子相比，学习或行为没有差异； 5) 如图所示外周代谢可导致循环血浆精氨酸的控制； 6) 精氨酸酶基因丢失表达导致神经元内在兴奋性和树突状结构的异常。在目标 1 中，长期将通过病毒载体基因治疗在肌肉中表达精氨酸酶 2，以检查生化和精氨酸酶缺乏的小鼠模型的表型校正。这种方法可以避免中和免疫无效突变患者的反应。在目标 2 中，研究将检验是否在支架上生长辅助肝脏可以提供导致高精氨酸血症表型纠正所需的最小尿素循环功能。这该方法可能对其他尿素循环障碍有效。随着拟议研究的成功完成预计一种基因和细胞替代的新疗法将为患有该病的患者迈出一步精氨酸酶缺乏症。

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）

GABAA receptors as plausible molecular targets and mediators for taurine and homotaurine actions.

GABAA 受体作为牛磺酸和同型牛磺酸作用的合理分子靶标和介质。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Meera, Pratap;Uusi;Lipshutz, Gerald S;Wallner, Martin
通讯作者：
Wallner, Martin

Guanidinoacetate (GAA) is a potent GABAA receptor GABA mimetic: Implications for neurological disease pathology.

胍基乙酸 (GAA) 是一种有效的 GABAA 受体 GABA 模拟物：对神经系统疾病病理学的影响。

DOI：
发表时间：
2023-05
期刊：
影响因子：
4.7
作者：
Meera, Pratap;Uusi;Wallner, Martin;Lipshutz, Gerald S
通讯作者：
Lipshutz, Gerald S

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

用于治疗中枢神经系统疾病的腺相关病毒基因疗法的免疫反应和免疫抑制策略：当前知识和方法。

DOI：
发表时间：
2022-12
期刊：
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

Lipid nanoparticle-targeted mRNA therapy as a treatment for the inherited metabolic liver disorder arginase deficiency.

脂质纳米颗粒靶向 mRNA 疗法用于治疗遗传性代谢性肝病精氨酸酶缺乏症。

DOI：
发表时间：
2019
期刊：
影响因子：
11.1
作者：
Truong, Brian;Allegri, Gabriella;Liu, Xiao;Burke, Kristine E;Zhu, Xuling;Cederbaum, Stephen D;Häberle, Johannes;Martini, Paolo G V;Lipshutz, Gerald S
通讯作者：
Lipshutz, Gerald S

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

O-GlcNAcylation 增强 CPS1 对氨的催化效率并促进尿素生成。

DOI：
发表时间：
2022-09-05
期刊：
影响因子：
16.6
作者：
Soria, Leandro R;Makris, Georgios;D'Alessio, Alfonso M;De Angelis, Angela;Boffa, Iolanda;Pravata, Veronica M;Rüfenacht, Véronique;Attanasio, Sergio;Nusco, Edoardo;Arena, Paola;Ferenbach, Andrew T;Paris, Debora;Cuomo, Paola;Motta, Andrea;Nitz
通讯作者：
Nitz

DOI：
{{ item.doi }}
发表时间：
{{ item.publish_year }}
期刊：
{{ item.journal_name }}
影响因子：
{{ item.factor }}
作者：
{{ item.authors }}
通讯作者：
{{ item.author }}

数据更新时间：{{ journalArticles.updateTime }}

作者：
{{ item.author }}

数据更新时间：{{ monograph.updateTime }}

作者：
{{ item.author }}

数据更新时间：{{ sciAawards.updateTime }}

作者：
{{ item.author }}

数据更新时间：{{ conferencePapers.updateTime }}

作者：
{{ item.author }}

数据更新时间：{{ patent.updateTime }}

Gerald S Lipshutz其他文献

Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia.

首次人体丙酸血症 1/2 mRNA 试验的中期分析。

DOI：
10.1038/s41586-024-07266-7
发表时间：
2024-04-03
期刊：
Nature
影响因子：
64.8
作者：
Dwight Koeberl;Andreas Schulze;Neal Sondheimer;Gerald S Lipshutz;T. Geberhiwot;Lerong Li;Rajnish Saini;Junxiang Luo;Vanja Sikirica;Ling Jin;Min Liang;Mary Leuchars;Stephanie Grunewald
通讯作者：
Stephanie Grunewald