Gene therapy for mitochondrial eye diseases

这项研究旨在证明使用基因编辑治疗与异质性线粒体DNA（mtDNA）突变相关的致盲性眼病的概念验证，这些疾病目前无法治疗。该提案建立在Minczuk实验室最近的突破基础上，该实验室利用靶向锌指核酸酶（mtZFN）降低致病性mtDNA水平，并恢复携带异质性tRNA突变的小鼠模型心脏中的生化和分子表型。在这里，我们的目的是确定是否mtZFN玻璃体内交付可以降低突变mtDNA水平和逆转的分子和功能表型在视网膜疾病的小鼠模型。这项研究将为mtZFN治疗线粒体眼病的临床潜力提供关键证据。此外，它将进一步验证这些基因编辑工具的使用，以纠正由异质性mtDNA突变引起的其他线粒体表型。

This study aims to demonstrate a proof-of-concept for the use of gene editing to treat blinding eye diseases linked to heteroplasmic mitochondrial DNA (mtDNA) mutations, which are currently untreatable. This proposal builds upon recent breakthroughs from the Minczuk laboratory utilizing mitochondrially targeted zinc-finger nucleases (mtZFNs) to reduce pathogenic mtDNA levels and restore biochemical and molecular phenotypes in the heart of a mouse model carrying a heteroplasmic tRNA mutation. Here we aim to determine whether mtZFNs delivered intravitreally can reduce mutant mtDNA levels and revert molecular and functional phenotypes in the retina in the disease mouse model. This study will provide crucial evidence about the clinical potential of mtZFNs to treat mitochondrial eye diseases. Moreover, it would further validate the use of these gene editing tools to correct other mitochondrial phenotypes caused by heteroplasmic mtDNA mutations.