Mitochondrial RNA transport as a novel therapy

描述(申请人提供)：典型的线粒体疾病是常见的和破坏性的疾病，预后极差。已经提出了基因治疗方法，包括从细胞核异位表达重新编码的线粒体基因。线粒体编码蛋白的极端疏水性仍然是此类疗法的技术障碍。我们提出了一种新的异位基因治疗方法，即RNA主动运输到线粒体进行翻译。我们已经开发了表达稳定的、可运输的RNA的载体，并将在体内测试它们的有效性。任何旨在将异位表达发展为基因治疗的严肃研究都需要在可服从的遗传系统中进行具有良好特征的致病内源性线粒体突变，在体内可以证明和优化其可行性。我们提出了一种使用生化和表型功能分析的严格的线粒体RNA运输测试，使用了一个特征良好的模型动物系统。 与公共卫生相关：线粒体疾病是破坏性的、无法治疗的疾病，每3-5000人中就有1人受到影响。我们建议进行临床前研究，以开发和证明一种新的RNA转运基因疗法的有效性。这一方法将利用已建立的线粒体疾病的无脊椎动物遗传模型在体内进行开发和测试。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Mitochondrial diseases are devastating untreatable diseases that affect ~ 1 in 3-5000 humans. We propose preclinical research to develop and demonstrate efficacy of a novel RNA transport gene therapy. This approach will be developed and tested in vivo using an established invertebrate genetic model of mitochondrial disease.