Development of Epigenetic Editors for Frataxin Reactivation

Epigenetic changes are genetic modifications that impact gene activity without changing the DNA sequence. Some epigenetic changes result in decreases in the activity of a gene and others in increases. Many studies have shown that frataxin gene expression is epigenetically silenced in FA and that modifying epigenetic marks can reverse FXN silencing. The discovery of CRISPR technology allowed scientists to not only edit the DNA sequence but also to make epigenetic modifications, expanding the available tools to affect gene expression. The versatility of epigenetic editing is however constrained, especially in the context of gene activation. Due to the limited number and large size of epigenetic editors, their therapeutic utility is severely restricted. Epicrispr developed a compact CRISPR-based gene modulation platform that is programmable and can alter the epigenome to achieve precise regulation of gene expression and impact human diseases. The group led by Dr. Daniel Hart, with support from Dr. Xiao Yang and Courtney Klappenbach, showed that these editors can reactivate silenced genes in vitro, and thereby providing an epigenetic solution to an epigenetic problem. Epicrispr’s editors are ultracompact and can be delivered with a single AAV, the same delivery method used in gene replacement approaches. With this grant, the Epicrispr team will test these editors for their abilities to reactivate FXN in cell models for human FA.