CRISPR Activates Silenced Genes to Treat Prader-Willi Syndrome

Duke University biomedical engineers have demonstrated a new approach for treating genetic diseases affecting large genomic regions. Using CRISPR, they activated a master epigenetic switch to turn on suppressed genes from one parent, compensating for defects in genes from the other parent. The research targeted Prader-Willi syndrome [pra-der-wil-ee], a genetic disorder causing constant hunger and other physical, mental, and behavioral issues. People with Prader-Willi syndrome have a missing region of a chromosome from their father, while the genes from their mother are naturally silenced through imprinting [im-print-ting], a process where one copy of a gene is inactive. Charles Gersbach [gers-bahk], the John W. Strohbehn Distinguished Professor of Biomedical Engineering at Duke, explained that this approach aims to activate the existing, but silenced, maternal genes. The team screened thousands of genomic targets, identifying sites that act as a "main power switch" for the silenced region. They used CRISPR to perform epigenetic manipulations, which alter gene expression without changing the DNA sequence. One successful approach involved DNA demethylation [dee-meth-il-ay-shun], which permanently activated the necessary maternal genes in stem cells that grew into neurons. Dahlia Rohm [rohm], a recent graduate, noted the exciting result of achieving a permanent effect from a transient CRISPR exposure, raising hopes for a durable therapy. The next steps involve animal studies to deliver the CRISPR system to neurons across large brain regions and ensure the epigenetic changes remain stable in mature neuronal cells. Josh Black [blak], a staff scientist at Duke, stated that manipulating a master controller of genes already present in the imprinted region is a more straightforward approach than delivering many different genes and RNAs through conventional gene therapy. The findings were published online in the journal *Cell Genomics* on February 12.