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Understanding the Mechanism and Preventing the Unique Neuropathology of Arginase Deficiency

了解精氨酸酶缺乏的机制并预防独特的神经病理学

基本信息

批准号：
9908195
负责人：
Gerald S Lipshutz
金额：
$ 34.13万
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：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908195
关键词：
Acids Acute Address Adoption Anatomy Animals Arginine Birth Brain Bystander Effect Cells Cerebral cortex Cessation of life Chronic Clinical Clinical Trials Congenital neurologic anomalies Creatine Data Disease Electrophysiology (science)Enzymes Etiology Exposure to Failure to Thrive Functional disorder Gene Expression Goals Growth Health Hepatic Hyperammonemia Hyperargininemia Impairment Inborn Errors of Metabolism Inequality Interneurons Intervention Knock-out Knockout Mice Laboratories Life Liver Measurable Measures Mediating Metabolism Microcephaly Motor Mus Myelin Neonatal Nervous System Trauma Neuraxis Neurologic Neuronal Dysfunction Neuronal Injury Neurons Oligodendroglia Pathogenesis Patients Periodicity Peripheral Pharmacology Plasma Play Psyche structure Recombinant adeno-associated virus (rAAV)Research Resolution Role Seizures Slice Synapses Synaptic Transmission Taurine Testing Toxin Urea cycle disorders arginase base central nervous system injury density dysmyelination excitatory neuron experimental study gene therapy improved infancy knockout animal leukodystrophy mouse model myelination nervous system disorder neuropathology novel therapeutics patch clamp postnatal prevent response restoration spasticity transmission process urea cycle

项目摘要

Project Summary/Abstract The overall goals of this project are to 1) investigate the etiology of the unique neuropathology associated with arginase 1 (A1) deficiency, a disorder of the urea cycle, and 2) to extensively demonstrate that AAV-based hepatic gene therapy is effective in preventing the features of this disorder as a prelude to a clinical trial. A1 deficiency results in chronic hyperargininemia characterized by progressive mental impairment, spasticity, and growth retardation, with only periodic episodes of hyperammonemia. Recent and preliminary findings from our laboratory with the A1-deficient mouse have demonstrated substantial anatomical, ultrastructural and electro- physiological differences between knockouts and wild types. A1 deficiency led to decreased intrinsic excita- bility, altered functional synaptic transmission, decreased dendritic arborization, dysmyelination and decreased synaptic density. The most likely mechanism causing these neuronal abnormalities is hyperarginine- or guani- dino compound-mediated dysfunction of neurons and oligodendrocytes. Controlling plasma arginine and guani- dino compounds following administration of liver-specific AAV-based gene therapy resulted in much of these measures being substantially improved. The finding abnormalities at the neuron, synapse, myelin, and circuit level have begun to elucidate the functional deficits in A1 deficiency. The identification of the proximate toxin and mechanism of neurodysfunction will open doors to potential pharmacological interventions for A1 deficiency in addition to gene therapy, and may open avenues to new therapies for other disorders where dysmyelination is a feature. Preliminary data: Our research group has (amongst other findings): 1) constructed and characterized the A1-deficient mouse; 2) demonstrated long-term survival with liver-specific recombinant AAV; 3) demonstrated that only low-level ureagenesis is necessary for survival; 4) shown that gene therapy- treated A1 knockout mice lack gross nervous system abnormalities; 5) shown that peripheral metabolism results in control of circulating plasma arginine; and 6) shown that loss of A1 gene expression results in abnormalities of intrinsic excitability, synapse type and number, myelination and the dendritic arbor of neurons. In Aim 1, the hypothesis that oligodendrocyte dysfunction and death result in dysmyelination and is in part the cause of neuronal dysfunction in A1 deficiency will be tested. In Aim 2, the hypothesis that elevated guanidino compounds can induce alterations in intrinsic excitability and synaptic transmission that are similar to those seen in A1 deficient animals will be tested. In Aim 3, it will be determined if A1 deficiency causes an imbalance in excitation and inhibition, and if this inequality is mainly through effects on perisomatic inhibition. Completion of these studies will provide a greater understanding of and the mechanism(s) behind the alterations in the brain, neurons, and synapses in A1 deficiency and hyperargininemia while demonstrating the efficacy of hepatic A1 gene therapy in preventing these abnormalities, providing strong evidence for this therapy as a prelude to its clinical adoption in patients with this progressive neurological disorder.

项目总结/文摘