Walter and Eliza Hall Institute Researchers Target SMCHD1 to Treat Prader-Willi Syndrome

New Gene Therapy Approach Restores Silenced Chromosome 15 Activity in Prader-Willi Syndrome

“Perhaps most importantly we didn’t find any untoward effects of targeting SMCHD1 in vivo, suggesting our approach might be both effective and safe,” Marnie Blewitt told Drug Discovery News. Researchers at the Walter and Eliza Hall Institute of Medical Research in Melbourne have successfully restored the activity of dormant maternal genes on chromosome 15 in preclinical models of Prader-Willi syndrome, offering a potential path toward a disease-modifying treatment for the rare genetic disorder.

Targeting the SMCHD1 Genetic Brake in Melbourne Laboratories

Prader-Willi syndrome arises when the paternal copy of chromosome 15 is deleted, while the maternally inherited genes remain healthy but silenced. In a study published in Science Advances, Marnie Blewitt’s laboratory at the Walter and Eliza Hall Institute investigated what happens when this silencing mechanism is removed. The team used antisense oligonucleotides, CRISPR gene editing, stem-cell, and genomic technologies to target the SMCHD1 protein, which acts as a genetic brake to keep the maternal genes switched off.

When researchers removed or inhibited SMCHD1 in patient-derived neural cells and mouse models, the dormant genes released their brake and woke up. Tracking thousands of genes across brain tissue like the hypothalamus revealed that this reactivation produced measurable physical and behavioral improvements. Affected mice showed enhanced social interaction, greater physical strength, and reduced body weight without exhibiting adverse side effects in other parts of the body.

Family Organizations and Global Research Support

The research effort received backing from organizations founded and led by families affected by the condition, including the Prader-Willi Research Foundation Australia and the Foundation for Prader-Willi Research USA. Kathlene Jones, CEO of the Prader-Willi Research Foundation Australia, emphasized the relentless daily challenges families face due to the intense drive to consume food associated with the disorder. A treatment addressing the root cause would prove transformational for the approximately 400,000 people worldwide living with the condition.

Additional financial support for the study came from the National Health and Medical Research Council, WEHI innovation funding, the Rebecca L. Cooper Medical Research Foundation, the Pamela and Lorenzo Galli Trust, the Brian M Davis Charitable Trust, and the Australian Government Research Training Program, alongside infrastructure backing from the Victorian Government. Building on these preclinical findings, the research team has formed a spinout company named Togglelux Therapeutics to advance SMCHD1-targeting therapeutics toward clinical development.

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