Epigenome Editing for Stable Reactivation of Maternal PWS Genes

Funding Summary

Dr. Gersbach continues his work examining advanced CRISPR tools to understand the regulation of gene activity in the PWS region and optimize gene activation strategies.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.

Lay Abstract

This proposal aims to develop a therapy for PWS, a rare neurodevelopmental disorder with no effective treatments. Due to an epigenetic phenomenon called genomic imprinting, certain genes on chromosome 15 are only expressed on the chromosome inherited from the father (paternal), while they are silenced on the chromosome inherited from the mother (maternal). PWS patients have lost the paternal copy of these genes but retain the intact, but silenced, maternal genes. Therefore, strategies to turn on these genes on the maternal chromosome provide a compelling therapeutic option. Our goal is to reactivate these silent maternal genes in a specific and stable manner using epigenome editing, a technology we have successfully used to regulate gene expression in other contexts. Epigenome editing provides the unprecedented opportunity to selectively and precisely turn genes ON or OFF by targeting the chemical modifications that control gene activity without altering the DNA sequence. This method is highly specific and avoids the risk of harmful mutations, offering a therapeutic path with unique advantages over conventional drugs and recent gene editing approaches. We have already demonstrated success in reactivating maternal silenced PWS genes, including SNRPN, PWAR6, and the snoRNAs SNORD116, SNORD109, and SNORD108, in PWS human pluripotent stem cells using our epigenome editing tools. We also have shown durable reactivation even after only a transient exposure of our epigenetic editing tools, demonstrating the feasibility of our approach. Our next step is to test this innovative epigenetic therapy in neurons as a direct approach to addressing PWS symptoms since PWS affects brain function. Aim 1 will determine if delivering our epigenetic editing strategy directly to neurons triggers maternal PWS gene activation or if additional factors are needed for activation and/or stability of activation. Aim 2 will identify factors responsible for the silencing of maternal PWS genes in neurons, determine ways to unlock this silencing with transient exposure to our dCas9-activator, and assess the alleviation of PWS-related symptoms in neurons. This knowledge is important for guiding therapeutic strategies for PWS and advancing the development of precise and efficient therapies for genetic disorders. Our proposed study is strengthened by a robust set of data, tools, and reagents that we recently generated, uniquely positioning us to achieve the ultimate goals of this proposal. Success could be truly transformative for PWS patients, potentially offering a one-time treatment to establish stable maternal gene activation for life.