A Protein Replacement Drug for Friedreichs Ataxia

弗里德里希共济失调（FA）是一种罕见的遗传性疾病，由基因重复引起，该基因阻止线粒体基质蛋白frataxin （FXN）的产生，FXN在线粒体铁稳态中起作用，特别是在铁硫簇蛋白的新生生物合成中。在缺乏它的情况下，游离铁在线粒体中积累，铁硫蛋白失去活性，并且由于电子传递链受损而无法产生能量。首席研究员开发了一种蛋白质替代方法，该方法使用细胞渗透肽将功能性FXN传递到线粒体基质。

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.