Prader-Willi Syndrome (PWS) is a rare and currently incurable neurodevelopmental disorder. Diagnosed at birth and initially characterised by severe muscle weakness, PWS children develop insatiable appetites and are faced with obesity challenges as well as a range of intellectual and developmental disabilities. All symptoms are thought to stem from a dysfunctional hypothalamus.
At the genetic level, PWS is an imprinting disorder, caused by the absence of genes on paternal chromosome 15, specifically in the region q11-q15. In a healthy individual the maternal genes in this region are silenced, and expression occurs exclusively from the paternal chromosome. PWS occurs when the normally expressed paternal genes are dysfunctional, usually because of a large deletion or maternal disomy event.
A potential therapeutic approach we are investigating to treat PWS postnatally is to activate PWS critical genes from the silenced maternal chromosome, specifically by targeting a known epigenetic repressor of the region called SMCHD1. Using patient derived iPSCs, we have chosen a DUAL-SMAD inhibition approach to generate neural progenitor cells from large deletion, maternal disomy and healthy patient lines. SMCHD1 disruption is achieved by using antisense oligonucleotides against SMCHD1, causing exon skipping and creating a dysfunctional protein.
Gene expression analysis from both 4 and 7-day knockdown time courses reveals subtle up-regulation of genes from the maternally imprinted PWS cluster; MAGEL2, MKRN3 and NDN and significant up-regulation of SNRPN. We see little to no change in UBE3A (repression of which may cause Angelman Syndrome) or nearby non imprinted genes.
Our initial results are promising and suggest that neonatal activation of the imprinted maternal allele could be a viable therapeutic approach for treating Prader-Willi Syndrome and that early intervention with a SMCHD1 inhibitor may provide some therapeutic benefit to those born with PWS as the brain continues to develop significantly after birth.