A Protein Replacement Drug for Friedreichs Ataxia

共济失调(FA)是一种罕见的遗传性疾病，是由阻止线粒体基质蛋白Frataxin(FXN)产生的基因重复引起的，FXN在线粒体铁稳态，特别是铁-硫簇蛋白的从头合成中发挥作用。在没有它的情况下，游离铁在线粒体中积累，铁硫蛋白失去活性，电子传输链受到破坏，能量生产无法产生。这位首席研究员开发了一种蛋白质替代方法，使用细胞穿透性多肽将功能性FXN传递到线粒体基质。 蛋白质替代疗法是治疗糖尿病、溶酶体储存障碍和血友病等代谢性疾病的成熟方法。在患者来源的细胞和动物模型中的工作已经证明，用TAT肽替换功能性FXN可以纠正FA疾病的表型。在小鼠模型中，TAT-FXN延长了寿命，纠正了组织学和生化缺陷，并改善了心脏和神经功能。此外，这个TAT蛋白输送平台可以扩展到FA之外，代表着一种有潜力治疗目前尚无治疗方法的多发性线粒体疾病的技术。 TRND项目团队正在合作开发和制造重组融合蛋白CTI-1601，进行更多的疗效和毒理学研究，并开发和验证评估CTI-1601所需的生化分析。成功完成这些研究将使合作者能够向食品和药物管理局提交研究性新药申请。

Friedreichs Ataxia (FA) is a rare genetic disease caused by repetitions in the gene that prevent production of the mitochondrial matrix protein frataxin (FXN), which functions in mitochondrial iron homeostasis, notably in the de novo biosynthesis of iron-sulfur cluster proteins. In its absence, free iron accumulates in mitochondria, iron-sulfur proteins lose activity and energy production fails through damage to the electron transport chain. The lead investigator has developed a protein replacement approach that uses a cell-penetrant peptide to deliver functional FXN to the mitochondrial matrix. Protein replacement therapy is a well-established approach to metabolic diseases, such as diabetes, lysosomal storage disorders and hemophilia. Work in patient-derived cellular and animal models has demonstrated that replacement of functional FXN using the peptide TAT can correct the FA disease phenotype. In a mouse model, TAT-FXN extends lifespan, corrects histology and biochemical defects, and improves cardiac and neurological function. Moreover, this TAT-protein delivery platform could be extended beyond FA, representing a technology with the potential to treat multiple mitochondrial disorders for which there are no current therapies. The TRND project team are collaborating to develop and manufacture the recombinant fusion protein CTI-1601, conducting additional efficacy and toxicology studies, and developing and validating the biochemical assays necessary to evaluate CTI-1601. Successful completion of these studies will enable the collaborator to submit an Investigational New Drug application to the Food and Drug Administration.