Mitochondrial RNA transport as a novel therapy

项目总结： 典型的线粒体疾病是一种常见的破坏性疾病 预后极差。基因疗法已经被提出，包括异体移植 重新编码的线粒体基因在细胞核中的表达。极端的 线粒体编码蛋白的疏水性仍然是实现这一目标的技术障碍 治疗。我们提出了一种新的异位基因治疗方法，其中RNA是 主动运输到线粒体进行翻译。我们已经开发出载体， 表达稳定的、可运输的RNA，并将在体内测试其有效性。任何严重的 旨在将异位表达发展为基因疗法的研究将需要 一种具有良好特征的、致病的、内源性线粒体突变 可以在体内证明和优化可行性的遗传系统。我们 提出了一种严格的线粒体RNA运输测试，使用生化和 使用具有良好特性的模型动物系统对功能进行表型分析。

Project summary: Archetypical mitochondrial diseases are common and devastating conditions with an extremely poor prognosis. Gene therapies have been proposed including allotopic expression of recoded mitochondrial genes from the nucleus. The extreme hydrophobicity of mitochondrial-encoded proteins remains a technical hurdle to such therapies. We propose a novel allotopic gene therapy approach where the RNA is actively transported into mitochondria for translation. We have developed vectors that express stable, transportable RNAs and will test their efficacy in vivo. Any serious investigation aimed at developing allotopic expression as a 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 RNA transport using both biochemical and phenotypic assays of function using a well-characterized model animal system.