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（由适用提供）：线粒体疾病是常见和毁灭性的疾病，预后极差。已经提出了基因疗法来将重新编码线粒体基因的同种异体表达从细胞核中进行，但是，这种方法的生存能力仍然存在争议。我们发现，这种方法限制了新基因疗法发展的主要技术障碍是从复合物中的内源性突变蛋白和这些蛋白质的疏水性竞争。我们发现了一种新型的线粒体翻译抑制（TLI）方法，可防止线粒体内突变蛋白的表达。我们建议测试线粒体TLI与一种新型治疗方法的组合，该方法将RNA靶向线粒体。这种方法使用新颖和以前未经测试的方法直接解决了技术障碍。任何旨在开发新的线粒体基因疗法的认真研究都需要在可融合的遗传系统中进行良好的，致病性的内源性线粒体突变，在体内可以证明和优化可行性。我们建议使用良好的特征性动物模型系统中的几种生化和表型测定，对线粒体TLI和线粒体靶向RNA的表达进行了严格的测试。