Project 2: Therapeutic Gene Editing for Friedreich's Ataxia

项目总结项目2 （frda）

PROJECT SUMMARY PROJECT 2 (FRDA) Friedreich's Ataxia (FRDA) is an autosomal recessive disorder characterized by progressive ataxia and damage to the nervous system, that is often associated with muscle weakness, spasticity, cardiomyopathy and diabetes mellitus. FRDA is caused by a deficiency in frataxin (FXN) protein levels that usually arises from a GAA-triplet repeat expansion in intron 1 of the FXN gene which results in transcriptional repression. The length of FXN GAA- repeats in the general population ranges from ~5-60, while FRDA patients may present with 66 to well over 1200 repeats, typically 600 to 900 repeats long. Long GAA-repeats undergo progressive instability in some somatic cell types that predominantly results in repeat expansion and consequently loss of FXN protein. The tissues that are affected in FRDA include the dorsal root ganglia (DRGs), the heart, and the pancreas. The onset of disease in patients is anticorrelated with the length of the shortest FXN allele, which typically presents at 10-15 years of age, though approximately 25% of patients have an atypical presentation with later disease onset. Although some symptoms can be ameliorated by physical therapy and surgery, no effective cure or treatment for the broader FRDA phenotype has yet been approved. The life expectancy for patients with FRDA is typically 40-50 years of age. In this follower project, we aim to improve FXN protein expression to enable rescue of disease progression in FRDA patients. Specifically, we aim to: (1) Optimize genome editing strategies to correct FRDA repeat expansion; (2) optimize genome editing strategies to correct FRDA repeat expansion in mice; and (3) perform pre-clincial IND enabling studies to assess safet and efficacy. We will work closely with the Gene Editing Core to develop the latest base editing and/or prime editing technologies in FRDA model systems. We will iterate with the Gene Editing Core to ensure that our genome editing tools maximize on-target editing efficiencies, minimize undesirable gene editing byproducts and off-target editing events, and maximize compatibility with in vivo delivery methods of potential therapeutic relevance.