Advance-CTR

Advance RI-CTR New Discovery Award

“Unlocking translational potential of epigenetic editing”

This is a critical study to unlock the translational potential of epigenetic editing.

The exciting paradigm of epigenetics that ‘genes are not your destiny’ has taken a novel turn with the development of ‘epigenetic editing’ approaches to selectively manipulate the status (e.g. promoter methylation) and thus the function (transcription) of genes. This methodology can resolve two major obstacles in health research. First, while epidemiological data show correlation of epigenetic changes in a plethora of divergent diseases, proof of causality for these methylation changes had been impossible. Second, there is a need for novel therapeutic strategies to specifically reverse the epigenetic alterations. 

The methodology Dr. Fedulov aims to develop has broad biomedical significance as a research causality tool in epigenetics and as a potential novel class of therapeutics. Demethylation of a silenced gene promoter opens it to situation-appropriate, context-dependent adaptive responsiveness to transcriptional stimuli, which is a great benefit vs. traditional overexpression or administration of extraneous protein. The key obstacle for future development and translation into humans is that currently the fusion demethylase constructs are dependent on lentiviral or similar genome integration step so that the target cell expresses them within. 

While such stable cell line is convenient for proof-of-concept experimentation, it is critical to make epigenetic editing not dependent of viral delivery to unlock its translational potential. This will be accomplished by producing purified proteins for administration in vivo. Epigenetic editing is a cutting-edge area; the study's aim to design, express, purify and test fusion proteins that without viral vectors permeate into nuclei, bind to specific DNA sequences and reduce methylation in the vicinity will produce a novel class of biologics and is thus a highly innovative, high-impact research.