# Hematopoietic Stem Cell Gene Therapy for Friedreich's ataxia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $344,531

## Abstract

Project Summary
Friedreich’s ataxia (FRDA) is a multi-systemic autosomal recessive disorder that is
predominantly caused by an homozygous GAA repeat expansion mutation within the
first intron of the frataxin (FXN) gene leading to a decrease of its expression. Frataxin is
a mitochondrial protein involved in iron metabolism. FRDA is characterized by ataxia,
neurodegeneration, muscle weakness, and cardiomyopathy. There is no treatment for
this lethal disease. We tested a new therapy for this disease consisting in wildtype (WT)
hematopoietic stem and progenitor cell (HSPC) transplantation in the Y8GR mouse
model of FRDA. This model expresses exclusively the mutated human FXN transgene,
thus mimicking the transcriptional deficiency seen in FRDA patients and the clinical
phenotype. The premise for using this strategy came from our previous data on
cystinosis, a multi-systemic lysosomal storage disorder, which was rescued by HSPC
transplantation via differentiation of the HSPCs into macrophages within tissues and
transfer of cystinosin-bearing lysosomes via tunneling nanotubes (TNTs) to the adjacent
diseased cells. TNTs can also transfer mitochondria, thus we hypothesized that this
strategy could also treat FRDA. This therapy worked quite beyond our expectation in
FRDA as the neurologic, muscular and cardiac complications were completely corrected
up to 7 months post-transplantation (latest time point tested) after a single infusion of
HSPCs in lethally irradiated Y8GR mice. Given the high risk of morbidity and mortality
associated with allogeneic HSPC transplantation, our objective is to develop an
autologous HSPC gene therapy approach for FRDA. Because overexpression of the
frataxin is toxic, we will test two different approaches to ex vivo gene-correct and restore
a physiologic expression of the gene in the HSPCs. One strategy will be to introduce in
HSPCs the human FXN (hFXN) cDNA under the control of a short form of its
endogenous promoter using a lentivirus vector. As most of the patients carry a GAA
repeat expansion, the second approach will be to use a CRISPR/Cas9-mediated gene
editing approach to remove this mutation in HSPCs. Human and murine FRDA HSPCs
will be used. Finally, we will also determine the ability of HSPC transplantation to reverse
preexisting complications. This work represents the first autologous gene-corrected
HSPC transplantation treatment strategy for FRDA and builds the foundation for a
clinical application of this strategy.

## Key facts

- **NIH application ID:** 9931316
- **Project number:** 5R01NS108965-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Stephanie Cherqui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $344,531
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931316

## Citation

> US National Institutes of Health, RePORTER application 9931316, Hematopoietic Stem Cell Gene Therapy for Friedreich's ataxia (5R01NS108965-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9931316. Licensed CC0.

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