"Most people can't conceive what daily life is like for a person living with Prader-Willi syndrome," said Kathlene Jones, CEO of the Prader-Willi Research Foundation Australia.
"Our children and adults have to navigate a world full of food they can't eat, while feeling an intense drive to consume it. That relentless pressure can bring great distress and very challenging behaviours that affect the whole family."
Now, researchers at Melbourne's Walter and Eliza Hall Institute of Medical Research (WEHI) have found a way to switch back on healthy genes that are silenced in the condition. This could lead to treatments that target the disorder's cause rather than its symptoms.
About 400,000 people worldwide live with Prader-Willi syndrome. It is a complex genetic condition that affects the brain and causes lifelong physical and developmental challenges, including developmental delays, intellectual disability and an insatiable appetite that can lead to obesity. People with the condition often depend on multiple medications, surgeries and specialist care. These treatments manage symptoms and provide limited relief.
The new study, published in Science Advances, focuses on a protein called SMCHD1, which WEHI discovered in 2008. SMCHD1 helps regulate gene activity. In Prader-Willi syndrome, it acts as a genetic "brake", keeping certain genes essential for development and brain function switched off.
The team used CRISPR gene editing, stem-cell, and genomic technologies to track what happened when SMCHD1 was removed. They measured the effects across thousands of genes and in the most disease-relevant brain tissue. In patient-derived cells and animal models, removing the protein released the brake and the dormant genes switched back on. WEHI describes the study as a world first.
Lead researcher Professor Marnie Blewitt, Deputy Director of WEHI and head of its epigenetics laboratory, said the key question had always been safety. Treatments would ultimately target babies and young children.
"We thought reactivating the 'sleeping' genes might be possible – what we didn't know was whether we could do it safely," she said.
"We now have the strongest evidence that removing SMCHD1 can restore gene activity lost in Prader-Willi syndrome without disrupting the rest of the body."
Prof Blewitt works closely with affected families and has seen the toll of the condition first-hand.
"I've seen children undergo multiple surgeries for scoliosis and met families whose lives revolve around medications, specialist appointments and managing often life-threatening symptoms," she said.
"Prader-Willi is one of the most complex medical conditions a family can face. That's why the possibility of a treatment that targets the root cause, rather than symptoms, is so significant."
Families helped make the research happen. The Prader-Willi Research Foundation Australia and the Foundation for Prader-Willi Research USA supported the study, and both were founded and led by families affected by the condition.
Ms Jones said the findings were an important step towards treatments that target the root cause.
"A treatment that addresses the root cause of the disease would be transformational. It could ease that burden for people living with PWS and bring relief to their families and carers.
"While still at an early stage, Professor Blewitt's work is a testament to what can be achieved when scientists and small, family-led patient organisations collaborate together."
For Prof Blewitt, the result caps nearly two decades of work that began when her team discovered SMCHD1.
"This is my life's work, so it's incredibly rewarding to finally see this approach succeed and bring hope to patients," she said.
"Watching those dormant genes 'wake-up' in both patient-derived stem cells and animal models was a powerful confirmation that the strategy works.
"It's exciting to see a fundamental discovery that began at WEHI now being developed locally and advancing towards potential new medicines, with the ultimate goal of helping those affected by this complex condition."
Melbourne-based Togglelux Therapeutics, a WEHI spinout focused on disease-modifying treatments for Prader-Willi syndrome, is now developing the approach into potential medicines.
Other supporters of the research were 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, with infrastructure support from the Victorian Government.