A research team has presented the results of their gene-editing study on patient-derived pluripotent stem cells (iPSCs) from patients with Friedreich ataxia (FA).

The study, presented at the 26th Annual Meeting of the American Society of Gene & Cell Therapy in Los Angeles, CA, this month, found that CRISPR/Cas9-mediated gene editing restored mitochondrial function and phenotype.

“We previously showed complete rescue of neurologic complications of FRDA in YG8R mice with a single, systemic infusion of wild-type hematopoietic stem and progenitor cells (HSPC), and rescue was mediated by FXN transfer from engrafted HSPC-derived microglia to diseased neurons,” the authors wrote. “We next developed an autologous stem cell transplantation approach using CRISPR/Cas9-mediated excision of GAA repeats in FRDA patients’ CD34+ HSPCs that increased frataxin expression and improved mitochondrial functions.”

In this study, the research team aimed to better understand FA neurodegeneration in terms of microglia and their interactions with neurons in the pathogenesis of FA. For this purpose, they generated 4 types of FA patient-derived iSPCs, which they transformed into neurons and microglia that displayed the typical mitochondrial fragmentation, increased superoxide production, and loss of membrane potential found in FA.

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They also generated CRISPR/Cas9-gene edited FA iPSCs without the GAA mutation in the frataxin (FXN) gene and turned them into microglia and cortical neurons to compare with the FA neurons and microglia.

Compared with the FA microglia, the edited microglia and those of healthy controls had normal characteristics. In addition to mitochondrial dysfunction, the FA neurons showed structural problems and signs of cell death, while the edited and control neurons did not.

The authors conclude that these two models help elucidate the role of microglia in FA neurodegeneration and highlight the potential rescue with the use of CRISPR/Cas9 gene-editing techniques.  


Mishra P, Sivakumar S, Johnson A, et al. Patient-derived iPSC-neurons and microglia for modeling Friedreich’s ataxia disease [abstract 1694]. Mol Ther. Published online May 1, 2023.