Mitochondrial RNA transport as a novel therapy

项目概要： 典型的线粒体疾病是常见的和破坏性的条件， 预后极差。已经提出了基因疗法，包括同种异体的 重新编码的线粒体基因从细胞核的表达。极端 但是，细胞质编码的蛋白质的疏水性仍然是这样的技术障碍。 治疗我们提出了一种新的异位基因治疗方法，其中RNA是 主动转运到线粒体中进行翻译。我们已经开发了载体， 表达稳定的、可转运的RNA，并将在体内测试它们的功效。任何严重 旨在开发异位表达作为基因疗法的研究将需要 在一个易受感染的，具有良好特征的，致病性的，内源性线粒体突变的 基因系统的可行性可以在体内证明和优化。我们 提出了一个严格的测试线粒体RNA运输使用生化和 使用良好表征的模型动物系统进行功能的表型测定。

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.