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AAV mediated gene knockdown of PIK3C2B as a therapeutic strategy for X-linked myotubular myopathy and fatty liver disease

AAV 介导的 PIK3C2B 基因敲低作为 X 连锁肌管肌病和脂肪肝的治疗策略

基本信息

批准号：
10753786
负责人：
JAMES J DOWLING
金额：
$ 19.66万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-18 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753786
关键词：
1-Phosphatidylinositol 4-Kinase Adult Affect American Animals Birth Body Weight decreased C2 Domain Cessation of life Charcot-Marie-Tooth Disease Chemicals Childhood Cirrhosis Clinical Data Dependence Deposition Development Diet Disease Endosomes Enteral Feeding Enzyme Inhibition Exercise Exploratory/Developmental Grant Facioscapulohumeral Facioscapulohumeral Muscular Dystrophy Fatty Liver Fatty acid glycerol esters Functional disorder Genes Genetic Goals Hepatobiliary Human In Vitro Individual Knock-out Knockout Mice Life Liver Liver Failure Liver diseases Malignant Neoplasms Malignant neoplasm of liver Mediating Metabolism MicroRNAs Modeling Molecular Mus Muscle Muscle hypotonia Natural History Neuromuscular Diseases Organ PIK3CG gene PMP22 gene Pathology Patients Phenocopy Phenotype Phosphotransferases Positioning Attribute Pre-Clinical Model Process Proteins RNA Reducing diet Regulation Reporting Risk Role Skeletal Muscle Survivors Symptoms Testing Therapeutic Therapeutic Uses Time Translating Translations Ventilator Vesicle Weight Gain Wheelchairs Wild Type Mouse X-linked myotubular myopathy clinical translation comorbidity delivery vehicle disability disease-causing mutation efficacy evaluation fatty liver disease gene therapy genetic approach improved in vivo infancy inhibitor insulin sensitivity knock-down knockout gene metabolic phenotype metabolic profile mouse model neurogenetics non-alcoholic non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutics overexpression patient subsets phosphatidylinositol phosphate 4-kinase prevent promoter rare condition success therapy development trafficking

项目摘要

PROJECT SUMMARY/ABSTRACT PIK3C2B encodes the class II PI3 kinase Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing beta (PIK3C2B) protein, a regulator of vesicle trafficking through the endosome. Mouse knockout of Pik3c2b has no overtly deleterious phenotype, but instead promotes a beneficial metabolic profile that includes reduced weight gain, improved insulin sensitivity, and, most relevant for this proposal, reduced fat deposition in the liver. In addition, we have previously shown that genetic reduction of Pik3c2b can both prevent and reverse the skeletal muscle phenotype, as well as extend survival, of the mouse model of X-linked myotubular myopathy (XLMTM). XLMTM is rare neurogenetic condition with onset in infancy that is associated with profound muscle related disabilities and early death. In addition to affecting the skeletal muscle, an emerging XLMTM phenotype is hepatobiliary disease, which progresses to liver failure in a subset of patients. There are no treatments for XLMTM. Importantly, liver disease has not previously been identified in pre-clinical models of XLMTM, a significant barrier for disease understanding and treatment. To overcome this barrier, in new data, we have developed the first mouse model of XLMTM liver disease. Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition that affects nearly 25% of American adults. It can lead to non-alcoholic hepatosteatosis (NASH), which in turn can progress to cirrhosis, liver failure, liver cancer, and death. There are no adequate therapies for these common and severe conditions. The scientific premise of this proposal is that reduction of PIK3C2B in mice promotes reduction of diet induced fatty liver and amelioration of disease relevant XLMTM phenotypes. The overall goal of the project is to develop therapies for XLMTM and NAFLD/NASH using a RNA knockdown based gene therapy. We hypothesize the following: (1) PIK3C2B knockdown in muscle and liver can be specifically, lastingly, and safely achieved with a synthetic miRNA delivered in vivo with AAV8 (AAV-miR-PIK3C2B); (2) AAV-miR- PIK3C2B can ameliorate both muscle and liver and phenotypes of the XLMTM mouse model; and (3) AAV-miR- PIK3C2B can prevent the development and progression of diet induce mouse NAFLD/NASH. These hypotheses will be rigorously evaluated in 3 aims. Aim 1 will develop AAV-miR-PIK3C2B, Aim 2 will test it in XLMTM mice, and Aim 3 will study it in a diet induced model of NASH. If successful, this proposal will be of high significance and impact because it will identify a single therapy suitable for clinical translation for both a rare, fatal paediatric condition and for a prevalent disease affecting millions of adults.

项目总结/文摘