In Prader-Willi syndrome — a rare genetic disease that leads to physical and metabolic changes and developmental delays — a group of genes on chromosome 15 inherited from the father are not expressed. The child still inherits the healthy versions from the mother, but they remain silent.
New research from Marnie Blewitt’s lab at the Walter and Eliza Hall Institute of Medical Research is investigating what happens if the maternal genes are switched back on. In a recent paper published in Science Advances, her team showed that using antisense oligonucleotides in mice and patient-derived neural cells to target the SMCHD1 protein, which is required to keep the maternal genes silenced, successfully restored the silenced gene activity. In mouse models of the condition, this led to improvements in social interaction, physical strength, and reduced weight.
“Perhaps most importantly we didn’t find any untoward effects of targeting SMCHD1 in vivo, suggesting our approach might be both effective and safe,” Blewitt told DDN.
Blewitt and her colleagues have now created a spinout company, Togglelux Therapeutics, to develop therapeutics that target SMCHD1 to treat Prader-Willi syndrome.
Removing the SMCHD1 protein
To find out what happens when SMCHD1 was removed from the brain, Blewitt’s team tracked effects across thousands of genes and brain tissue like the hypothalamus. They found that the removal led to improved phenotypes in the mouse model — without leading to other side effects elsewhere in the body.
“At this stage we can’t see any disadvantages. But of course, as we continue to investigate targeting SMCHD1, we are always investigating whether this will be a safe approach. To date, we haven’t observed any concerning effects by targeting SMCHD1 in animals or in cellular models at this stage,” said Blewitt.
The first treatment targeting the root cause
Blewitt noted that the most exciting part of this work, which she said the team has been working on for about nine years, is the potential to help people living with Prader-Willi syndrome and their families.
“It is a devastating disorder, and anything we can do to target the underlying cause of disease will improve the quality of life for these individuals and their families. With our current data, we feel that this will be possible, and that brings incredible hope for our team,” she said.
Through Togglelux Therapeutics, their team could now create the first disease-modifying therapy for this rare disease.
