Molecular prostheses for mitochondrial disorders

描述(申请人提供)：线粒体遗传障碍是最常见的先天性新陈代谢错误集合，影响超过1：4000的活产婴儿。他们的特点是呼吸链的遗传性缺陷，这种缺陷的阻断会导致多系统器官衰竭和不可避免的死亡。尽管在阐明这些疾病的分子基础方面已经取得了巨大的进展，到目前为止已经发现了100多个疾病基因，但没有一种治疗方法被证明是有效的。由于在这些疾病中可能会有如此多的不同基因发生突变，传统的酶替代疗法不太可能是一种有用的方法。我们提出了一种潜在的仿制药治疗策略，旨在针对线粒体疾病中改变的常见生化途径。我们的方法是受自然的启发：一些微生物、原生动物和真菌已经进化出相对简单的生化创新，使它们能够在没有呼吸链的情况下生存。我们建议使用计算基因组学来系统地扫描数千个已测序的细菌基因组，以识别那些缺乏完整呼吸链的细菌，然后使用生物信息学、细菌遗传学和化学生物学的组合来系统地识别使它们能够在没有完整呼吸链的情况下生存的蛋白质和小分子。我们将创建这样一个多肽和天然产物的库，并在人类线粒体疾病的细胞模型中评估它们缓解病理的能力。如果成功，这个项目将产生一整条小分子和蛋白质管道，可能代表着治疗这些疾病的新一类疗法的起点。 公共卫生相关性：线粒体呼吸链疾病统称为最常见的新陈代谢先天错误。估计患病率为1：4000活产儿。这些疾病可能出现在儿童或青壮年，很难诊断和处理。目前还没有一种有效的治疗方法。拟议的项目旨在开发一种治疗这些疾病的新方法。

DESCRIPTION (provided by applicant): Genetic disorders of the mitochondrion represent the most common collection of inborn errors of metabolism, impacting over 1:4000 live births. They are characterized by an inherited defect in the respiratory chain, whose blockade leads to multisystem organ failure and inevitable death. Although there has been tremendous progress in elucidating the molecular bases of these disorders, with over 100 disease genes identified to date, not a single therapy has been proven to be useful. Because so many different genes can be mutated in these disorders, traditional enzyme replacement therapy is unlikely to be a useful approach. We propose a potentially generic therapeutic strategy that that aims to target the common biochemical pathway that is altered in mitochondrial disorders. Our approach is inspired by nature: a number of microbes, protozoa, and fungi have evolved relatively simple biochemical innovations that allow them to survive without respiratory chains. We propose to use computational genomics to systematically scan the thousands of sequenced bacterial genomes to identify those lacking complete respiratory chains, and then to use a mix of bioinformatics, bacterial genetics, and chemical biology to systematically identify the proteins and small molecules that endow them an ability to survive without a complete respiratory chain. We will create a library of such polypeptides and natural products and evaluate their ability to alleviate pathology in human cellular models of mitochondrial disease. If successful, this project will yield an entire pipeline of small molecules and proteins that may represent the starting point for a new class of therapeutics for these disorders. PUBLIC HEALTH RELEVANCE: The mitochondrial respiratory chain disorders collectively represent the most common inborn error of metabolism. The prevalence is estimated to be 1:4000 live births. These disorders can present in childhood or in young adulthood and are difficult to diagnose and manage. At present there is not a single proven therapy. The proposed project aims to develop a new therapeutic approach to these disorders.