CRISPR used to switch on suppressed genes in Prader-Willi syndrome

Gene silencing that causes Prader-Willi syndrome (PWS) can be efficiently undone by using CRISPR-based epigenome editing, new research has revealed.

PWS is a rare genetic disorder causing excessive appetite (which in turn leads to medical issues associated with obesity), limited growth, and cognitive impairment. A research team at Duke University, North Carolina, developed a method to reactivate the PWS gene in human induced pluripotent stem (iPS) cells derived from PWS patients, without modifying the DNA sequence.

'There aren't really any therapies for [PWS] right now, but these people already have copies of all the genes they need, we just need to figure out a way to turn them on' said Charles Gersbach, professor of biomedical engineering at Duke University, and senior author of the study published in Cell Genomics.

Humans generally inherit two copies of each genetic locus (the physical location of a gene on a chromosome), one from each parent. The genes at certain loci are silenced depending on their parental origin, through a process known as imprinting. In PWS, the genetic locus inherited from the father is deleted while the gene at corresponding locus inherited from the mother is silenced, resulting in a complete lack of proteins encoded at that locus.

Professor Gersbach added: 'There are many examples of these imprinted regions of the genome, where one copy of a set of genes from either parent is normally silenced. But problems occur when a mutation causes people to lose the complementary active genes from the other parent.'

The CRISPR system developed in this study used two independent strategies. In the first one, CRISPR was fused with a molecule that strongly activates genes. In the second one, it was combined with a molecule that removes methyl marks from DNA, promoting the access of the genome decoding machinery. The authors monitored the expression of the PWS locus and detected an increase in expression of the maternal locus.

This research represents a promising avenue for the treatment of PWS, and could potentially be applied to other genetic diseases that occur in a similar way. However, further studies are needed in living organisms, in order to assess the effectiveness of the approach in contexts that more closely resemble a human body.

'If you wanted to treat this disease through conventional gene therapy, you'd have to deliver many different genes and RNAs,' explained Joshua Black, PhD student at Duke University who is mentored by Professor Gersbach and coauthored the paper. 'Our approach to manipulate a master controller of all of these genes that are already present in the imprinted region is a much more straightforward option. This is really an ideal use case for the epigenome editing technology we have been focused on.'