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Development of Molecular Therapy for Carbamoyl Phosphate Synthetase Deficiency

氨基甲酰磷酸合成酶缺乏症分子治疗的进展

基本信息

批准号：
8996735
负责人：
Gerald S Lipshutz
金额：
$ 23.1万
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：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8996735
关键词：
Address Adult Affect Ammonia Animal Behavior Animal Model Animals Anorexia Astrocytes Birth Brain Injuries Breeding Carbamoyl-Phosphate Synthase (Ammonia)Carbamyl Phosphate Cell division Cells Cerebral Edema Cessation of life Codon Nucleotides Coma Complementary DNA DNA Sequence Alteration Data Defect Dependovirus Development Diet Disease Disease model Drug Metabolic Detoxication Encephalopathies Endothelium Environment Enzymatic Biochemistry Enzymes Episome Functional disorder Future Gene Delivery Gene Transduction Agent Genes Genetic Genetic Recombination Goals Health Hemophilia A Hepatic Hepatocyte Human Hyperammonemia Hyperargininemia Hypercapnic respiratory failure Immune response Impairment In Vitro Inborn Genetic Diseases Incidence Individual Infant Inherited Knock-out Knockout Mice Laboratories Left Ligase Link Liver Mammals Mental Retardation Metabolic Diseases Metabolic Pathway Metabolism Methods Modeling Molecular Morbidity - disease rate Mus N acetyl L glutamate Neonatal Neurologic Nitrogen Organ Pathway interactions Play Polyadenylation Population Posture Procedures Proteins Psyche structure Recombinant adeno-associated virus (rAAV)Recombinants Recruitment Activity Research Risk Role Saimiriine Herpesvirus 2 Seizures Series Signal Transduction Site Tamoxifen Technology Testing Time Transgenes Transgenic Mice Viral Viral Genes Viral Genome Viral Vector Work adeno-associated viral vector base behavioral study carbohydrate metabolism enzyme deficiency gene correction gene replacement gene therapy gutless adenoviral vector improved in vivo lipid metabolism liver transplantation mortality mouse model natural hypothermia nerve injury novel novel therapeutics pre-clinical promoter protein metabolism small molecule therapy development tool transgene expression urea cycle vector wasting

项目摘要

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.

描述：尿素循环是哺乳动物氨解毒的主要途径。氨基甲酰磷酸合成酶 1 (CPS1) 缺乏症是一种毁灭性的疾病。在人类中，缺乏这种酶的临床特征是周期性发生高氨血症，导致进行性精神障碍和死亡的可能性很高。该提案旨在描述该疾病的新动物模型，并开发利用病毒载体基于基因纠正氨基甲酰磷酸合成酶缺陷的方法。初步数据：我们的研究小组已经：1）正在开发条件性CPS1缺陷型基因敲除小鼠； 2) 在患有肝细胞内和分泌蛋白疾病的动物新生儿中施用后，重组辅助依赖性腺病毒载体和腺相关病毒载体的转基因均表现出短期和长期表达，从而导致遗传校正（A型血友病和精氨酸酶缺乏症）。在目标 1 中，我们将描述一种新型氨基甲酰磷酸合成酶 I 缺陷的条件性敲除小鼠模型，该模型将有助于开发针对这种疾病的疗法；在目标 2 中，我们将开发新型基因治疗载体作为 CPS1 缺陷的基因替代策略。这些研究将为开发 CPS1 缺陷的基因校正方法提供重要的新工具，并提供小动物模型来研究近端尿素循环障碍中高氨血症以外的脑损伤机制。