Preprint identifies SMCHD1 as a candidate target for gene-activation therapy in Prader-Willi syndrome
A bioRxiv preprint reports that inhibiting the epigenetic regulator SMCHD1 can reactivate silenced maternal copies of genes in the Prader-Willi syndrome imprinted locus in cellular and animal models.
A preprint posted to bioRxiv (14 May 2026) proposes SMCHD1 — a structural maintenance of chromosomes hinge domain-containing protein that contributes to epigenetic silencing — as a novel target for gene-activation therapy in Prader-Willi syndrome (PWS).
PWS is a neurodevelopmental disorder caused by lack of expression from the paternal copy of an imprinted gene cluster on chromosome 15q11-q13, most commonly due to paternal deletion, maternal uniparental disomy, or an imprinting defect. All affected individuals retain a silenced maternal copy of the same genes. The therapeutic hypothesis explored in this preprint is that reactivating the maternal copy could restore sufficient gene expression to ameliorate disease.
The authors show in cellular models and preliminary in vivo experiments that SMCHD1 contributes to silencing of the maternal PWS-associated genes, and that its inhibition can partially restore expression. They propose this as a proof-of-concept for a gene-activation rather than gene-replacement approach.
This preprint has not yet been peer-reviewed. The experimental work is at an early stage and does not constitute a therapeutic proposal for clinical application. Researchers working on imprinting disorders, epigenetic therapies, and rare neurodevelopmental conditions will find the mechanistic findings of interest. For genetic counsellors supporting families affected by PWS, the broader landscape of therapeutic research in this area is relevant context.
Plain-language version
For patients, families, and general readers. Educational only — not medical advice.
Prader-Willi syndrome (PWS) is a genetic condition that occurs when a set of genes on chromosome 15 — inherited from the father — is missing or not working properly. Every person with PWS also has a working copy of those genes from their mother, but it is normally switched off by a process called imprinting. A new piece of research — not yet reviewed by other scientists — suggests that a protein called SMCHD1 helps keep this maternal copy switched off. When researchers reduced SMCHD1 activity in the laboratory, some of those silenced genes began to switch back on again. This is very early research in cells and animal models. It does not mean a treatment is available, but it adds to scientists' understanding of how PWS works at a molecular level. This is an educational summary, not medical advice. If anything here raises questions for you, please speak with your GP or a clinical professional.
Sources
Read the original reporting — these are the public sources this summary draws from.
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Primary sourcePreprint bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-14SMCHD1 is a novel target for gene-activation therapy to treat Prader-Willi Syndrome