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.

Public Health Relevance

Friedreich?s ataxia (FRDA) is a lethal hereditary disease characterized by ataxia, neurodegeneration, muscle weakness, and cardiomyopathy and for which there is no treatment. Using a mouse model of FRDA, we showed that hematopoietic stem and progenitor cell (HSPC) transplantation could lead to the complete rescue of the disease. We now propose to develop the optimal strategy to gene-correct FRDA HSPCs and to test their ability to reverse existing complications in the prospect of a future clinical application of this strategy for FRDA.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Gubitz, Amelie
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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