Pre-clinical studies of novel mitochondrial gene therapies

新型线粒体基因疗法的临床前研究

基本信息

批准号：
9212818
负责人：
Michael John Palladino
金额：
$ 28.69万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2015-04-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212818
关键词：
Address Affect Animal Model Animals Biochemical Biological Assay Biological Models Biology Cell Nucleus Cell model Cells Code Communities Complex Data Dependence Development Dimerization Disease Engineering Genes Genetic Genetic Models Genetic Transcription Genetic Translation Human Hydrophobicity In Vitro Internal Ribosome Entry Site Invertebrates Investigation Length Location Mammalian Cell Measures Messenger RNA Methods Mitochondria Mitochondrial Diseases Mitochondrial Encephalomyopathies Mitochondrial RNA Mono-S Mutation Pathogenicity Pharmacotherapy Phenotype Process Proteins RNA Resistance Small RNA Structure System Testing Therapeutic Transfer RNA Translation Initiation Translations base design dimer gene therapy in vitro Model in vivo mitochondrial genome mitochondrial messenger RNA mutant novel novel strategies novel therapeutic intervention outcome forecast pre-clinical research preclinical study prevent protein expression public health relevance tool translational approach vector

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial diseases are common and devastating conditions with an extremely poor prognosis. Gene therapies have been proposed involving allotopic expression of recoded mitochondrial genes from the nucleus, however, the viability of such an approach remains controversial. We have discovered that the major technical hurdles to such an approach that limit the development of a novel gene therapy are competition from the endogenous mutant protein in the complex and the hydrophobicity of these proteins. We have discovered a novel mitochondrial translation inhibition (TLI) approach to prevent expression of the mutant protein within mitochondria. We propose to test the combination of mitochondrial TLI with a novel therapy approach that targets coding RNAs to mitochondria. Such an approach directly addresses both technical hurdles using novel and previously untested methods. Any serious investigation aimed at developing a novel mitochondrial gene therapy would require a well-characterized, pathogenic, endogenous mitochondrial mutation in an amenable genetic system where feasibility can be demonstrated and optimized in vivo. We propose a rigorous test of mitochondrial TLI and mitochondrial-targeted RNA expression using several biochemical and phenotypic assays of function in a well-characterized animal model system.

描述（由申请人提供）：线粒体疾病是一种常见且具有破坏性的疾病，其预后极差。已经提出了从细胞核中同位素表达重新编码的线粒体基因的基因疗法，但是我们发现这种方法的可行性仍然存在争议。限制新型基因疗法开发的这种方法的主要技术障碍是复合物中内源突变蛋白的竞争以及这些蛋白质的疏水性。我们发现了一种新的线粒体翻译抑制。我们建议测试线粒体 TLI 与靶向编码 RNA 至线粒体的新型治疗方法的组合，这种方法使用新颖且以前未经测试的方法直接解决了这两个技术障碍。任何针对新型线粒体基因疗法的认真研究都需要在一个合适的遗传系统中进行充分表征的致病性内源性线粒体突变，在体内可以证明和优化可行性。我们建议对开发线粒体 TLI 和线粒体靶向进行严格的测试。在充分表征的动物模型系统中使用多种生化和表型功能测定进行 RNA 表达。