Engineering Epigenome Editing Tools For Sustained Reactivation of Maternal PWS Genes

Funding Summary

Dr. Iglesias has been working on potential genetic therapies for Prader-Willi syndrome and has shown that ‘epigenome editing’ can reactivate the maternal genes in the PWS region in human cells. The current study will focus on determining the molecular requirements to permanently reactivate the maternal genes in the PWS region, so that gene expression is maintained long-term in the cells.

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

Lay Abstract

This proposal investigates the development of a potential genetic therapy for PWS. PWS is caused by the loss of a part of human chromosome 15 (PWS region 15q11-q13) passed down by the father, resulting in a lack of expression of genes in the PWS region. Humans have two sets of chromosomes, one from the mother (maternal) and one from the father (paternal). Typically, genes are expressed from both sets of chromosomes. However, due to a phenomenon called genetic imprinting, several genes in the PWS region are only expressed on the paternal chromosome while they are silenced on the maternal chromosome. People with PWS have lost the active paternal PWS region but still have the inactive but otherwise healthy genes on the maternal chromosome that would be fully functional if reactivated. Our objective is to selectively reactivate maternal gene expression in the PWS region in a sustained and heritable manner using a recently developed technology called epigenome editing. This technology, which is extensively used in our lab, provides the unprecedented opportunity to selectively turn genes ON or OFF using specially designed proteins. Our strategy presents a therapeutic path that offers unique advantages over conventional pharmaceutical drugs or recent gene editing approaches, as it is a targeted, highly-specific therapy with precise control over gene expression that does not result in changes to the DNA sequence, eliminating the risk of permanent off-target mutations. As a proof of concept, our preliminary data show that we are indeed able to reactivate the silenced PWS genes on the maternal chromosome in human cells using epigenome editing. This proposal builds upon these preliminary data to unravel the features and requirements that would lead to the permanent reactivation of the maternal PWS region in human cells. This will provide an opportunity for therapeutic intervention by replacing gene expression that is lost from the paternal allele. Our proposed study is strengthened by a host of data sets, tools, and reagents that we recently generated that uniquely position us to achieve the ultimate goals of this proposal. If successful, this approach will lay the groundwork towards the therapeutic development of a one-time gene therapy establishing stable reactivation of PWS genes for the lifetime of the patient.