Can immune cells of the brain be used to rescue neurons in FA?

The overall goal of this project is to investigate the role and contribution of microglia (resident immune cells in the brain) to FA pathology. Dr Cherqui and her collaborators have previously shown in a mouse model of FA that transplantation of wild-type hematopoietic stem and progenitor cell (HSPC) completely corrected the neurologic, muscular, and cardiac complications. It is believed that transplanted HSPCs differentiate into microglia/macrophages, a type of resident immune cells in the brain and other tissues. They have previously shown that tissue rescue was at least partly mediated by the transfer of frataxin from HSPC-derived microglia-like cells to diseased neurons, but the exact mechanism of rescue, including how microglial replacement and frataxin transfer from microglia-like cells to neurons contributes to this rescue is still unknown. These investigators believe that the impressive response of the FXN-expressing HSPC transplant is due to not only the transfer of frataxin to neurons but also to the rescuing function of microglia. They will utilize novel in vitro and in vivo methods, including patient-derived organoids (mini-brains) and a mouse model of human microglia, to ascertain the microglial contribution to FA pathogenesis and the potential for gene editing to correct this phenotype. This project will provide supporting evidence that CRISPR-edited HPSC transplantation can be used to treat FA and will advance the understanding of microglia-neuron interactions.

Related Research Publications

PubMed | May 2022

Advantages and Limitations of Gene Therapy and Gene Editing for Friedreich's Ataxia

Anusha Sivakumar, Stephanie Cherqui