# Project 2: Therapeutic Gene Editing for Friedreich's Ataxia

> **NIH NIH U19** · JACKSON LABORATORY · 2024 · $644,886

## Abstract

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.

## Key facts

- **NIH application ID:** 10842412
- **Project number:** 5U19NS132304-02
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** DAVID R LIU
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $644,886
- **Award type:** 5
- **Project period:** 2023-05-16 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842412

## Citation

> US National Institutes of Health, RePORTER application 10842412, Project 2: Therapeutic Gene Editing for Friedreich's Ataxia (5U19NS132304-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10842412. Licensed CC0.

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