Cells heal themselves: gene-edited hematopoietic stem cells restore frataxin deficiency in multiple organs.

Abstract

Friedreich's ataxia (FRDA) is a triplet repeat expansion disorder with multisystem, progressive symptoms caused by reduced frataxin protein levels and compromised mitochondrial function. Restoration of frataxin protein is a focus of clinical trials involving adeno-associated viral vectors, but substantial barriers exist because of the immune response they elicit. In this issue of the JCI, Sivakumar et al. harnessed CRISPR/Cas9 editing of endogenous hematopoietic stem and progenitor cells (HSPCs) to excise the frataxin gene (FXN) repeat expansion ex vivo, followed by autologous transplantation. A single, systemic infusion of corrected HSPCs resulted in long-term engraftment and sustained multiorgan benefit in a humanized mouse model of FRDA. This improvement in brain, cardiac, and pancreatic symptoms, mediated by myeloid progeny of the engrafted stem cells, provides strong support for the potential effectiveness of this approach in humans and bypasses the need to correct the FXN deficiency in the affected tissue and cells directly.