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

• 批准号: 8872239
• 负责人: Gerald S Lipshutz
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8872239
• 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; carbamoyl phosphate synthetase deficiency; carbohydrate metabolism; enzyme deficiency; gene correction; gene replacement; gene therapy; helper-dependent adenoviral vector; improved; in vivo; lipid metabolism; liver transplantation; mortality; mouse model; natural hypothermia; nerve injury; novel; pre-clinical; promoter; protein metabolism; public health relevance; small molecule; therapy development; tool; transgene expression; urea cycle; vector; wasting

 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) 缺乏对人类来说是一种毁灭性的疾病，这种酶缺乏的临床特征是周期性出现高氨血症，导致进行性精神障碍和精神障碍。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 缺陷型敲除小鼠；2) 证明重组辅助依赖性腺病毒载体和腺相关病毒载体在新生儿后可短期和长期表达转基因。在患有细胞内和肝脏分泌蛋白疾病的动物中给药，导致遗传校正（A型血友病和精氨酸酶缺乏症）在目标1中，我们将描述一种新的条件条件。建立氨基甲酰磷酸合成酶 I 缺陷的小鼠模型，这将有助于开发针对这种疾病的敲击疗法；在目标 2 中，我们将开发新的基因治疗载体作为 CPS1 缺陷的基因替代策略。方法用于基因校正 CPS1 缺陷，并提供小动物模型来研究近端尿素循环障碍中高氨血症之外的脑损伤机制。