Friedreich's ataxia (FRDA) is a multi-systemic autosomal recessive disorder that is predominantly caused by a homozygous GAA repeat expansion mutation within intron 1 of the frataxin gene (FXN) leading to a decrease of its expression. FXN is a mitochondrial protein involved in iron metabolism. FRDA is characterized by ataxia, neurodegeneration, muscle weakness, and cardiomyopathy. There is no cure for this lethal disease. We are proposing to treat FRDA by hematopoietic stem and progenitor cell (HSPC) transplantation. This hypothesize is based on our previous work on cystinosis, which is a lysosomal storage disorder leading to multi-organ degeneration. Using the mouse model for cystinosis, we showed that transplantation of wild-type HSPC resulted in abundant bone marrow-derived tissue engraftment, robust tissue cystine reductions and long-term tissue preservation. One of the mechanisms underlying this surprising effect involves the differentiation of HSPCs into macrophages that provides healthy lysosomes carrying the functional protein cystinosin to the host disease cells via tunneling nanotubes (TNTs). Mitochondria can also be transferred via TNTs. Therefore, we believe that HSPC transplantation will allow the delivery of healthy mitochondria bearing fxn to the damaged tissues and will represent a life-long therapy that will prevent the long-term complications associated with FRDA. As a model for FRDA, we will use the YG8R mouse model, which is currently considered the best animal model of FRDA as it expresses only the human mutated frataxin containing GAA repeats, without endogenous murine frataxin, and develop symptoms similar to the human pathology.
In Specific aim 1, we propose to test the therapeutic impact of HSPC transplantation in the YG8R mice. HSPCs will be isolated from eGFP-transgenic mice, so the cells can be tracked after transplantation, and will be transplanted in lethally irradiated YG8R mice at 2 month-old. The first objective will be t verify if bone marrow-derived cells engraft in the affected tissues, especially within the central nervous system, heart and skeletal muscle, and to characterize their phenotype. The second objective will be to evaluate the impact of HSPC transplantation on the mouse phenotype by behavioral testing, and histological and biochemical analyses.
In Specific aim 2, we will investigate mitochondrial cross-correction in the context of FRDA in vitro and in vivo. We will generate the DsRed mtGFP-Tg transgenic mice expressing ubiquitously the DsRed reporter gene in the cytoplasm and eGFP in mitochondria by breeding available transgenic mice. HSPCs will be isolated from these mice and transplanted into YG8R mice. Tissues will be analyzed by confocal microscopy analysis to visualize if a transfer of eGFP-expressing mitochondria occurs from the DsRed bone marrow-derived cells to the host cells. Macrophages and fibroblasts will be isolated from the DsRed mtGFP-Tg mice and the YG8R, respectively, to study mitochondrial transfer in vitro and the resulting cellular and phenotypic outcomes. This work has the potential to lead to a new treatment for FRDA and be a proof of concept for other mitochondrial disorders.

Public Health Relevance

Friedreich's ataxia is a lethal hereditary disease characterized by ataxia, neurodegeneration, muscle weakness, and cardiomyopathy and for which there is no cure. We propose a new treatment strategy for this disease based on the use of adult bone marrow stem cells. If successful, this work has the potential to lead to a new treatment for Friedreich ataxia and be a proof of concept for other mitochondrial disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Gwinn, Katrina
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University of California San Diego
Schools of Medicine
La Jolla
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Cherqui, Stephanie; Courtoy, Pierre J (2017) The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives. Nat Rev Nephrol 13:115-131
Ariazi, Jennifer; Benowitz, Andrew; De Biasi, Vern et al. (2017) Tunneling Nanotubes and Gap Junctions-Their Role in Long-Range Intercellular Communication during Development, Health, and Disease Conditions. Front Mol Neurosci 10:333
Rocca, Celine J; Goodman, Spencer M; Dulin, Jennifer N et al. (2017) Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich's ataxia. Sci Transl Med 9:
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