Can CRISPR Offer a Cure for Prader-Willi Syndrome?
Naturally suppressed genes turned on by CRISPR technology offer cure hopes for rare diseases.
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Prader-Willi syndrome (PWS) is a rare genetic disease that causes a wide range of physical, mental and behavioral problems, most notably a constant sense of hunger. PWS has a birth incidence of 1 in 10,000–30,000, with the global prevalence of PWS ranging from 1–9 per 100,000 individuals, affecting between 350,000–400,000 individuals worldwide.
Recent research from Duke University has demonstrated a promising new approach that could be used to treat a rare and complex class of genetic diseases, such as PWS, caused by defects in a relatively large region of the genome.
By identifying and activating a master epigenetic switch using CRISPR gene technology, the researchers showed they can turn on many naturally suppressed genes from one parent to compensate for defects in the same genes provided by the second parent. The results were published in the journal Cell Genomics.
What is PWS?
PWS is associated with a large range of symptoms that significantly negatively affect the quality of life for affected individuals and their families. PWS impacts are multifaceted as they stem from a person missing an entire region of a chromosome containing many different genes with many different functions. There is currently no cure for PWS, so treatment aims to manage the symptoms and associated difficulties.
The disease causes people to want to eat all the time due to their appetite never being satiated – leading to a whole host of issues associated with weight gain. It also causes defects in growth and physical development, cognitive impairment, speech problems, distinct facial features and many more effects.
In PWS, the associated genes are only missing from the father’s side of the genetic equation. Individuals with PWS still carry the requisite genes from the mother, but in healthy individuals, those genes are naturally silenced via a mechanism called imprinting.
“For most of our genes, we inherit one copy from our father and one from our mother – the paternal and maternal chromosomes,” Dr. Charles Gersbach, the John W. Strohbehn Distinguished Professor of Biomedical Engineering at Duke University, told Technology Networks.
“Some of these genes are controlled in a way such that only the paternal or maternal copy is used – the silencing of the unused gene is a phenomenon known as imprinting. Imprinting occurs by making chemical modifications to the DNA to turn off that gene, but those modifications are reversible,” he continued.
The problem occurs when a mutation causes the loss of complementary active genes from the other parent. Currently, there aren’t any therapies for treating this, but individuals with PWS already have all the genes they need – they just need to be turned on.
Identification of a master epigenetic switch in PWS
The researchers applied CRISPR gene technology to investigate whether activating an entire region of genes silenced through imprinting was possible. While the original CRISPR system carries a protein called Cas9 that slices targeted viral genomes, the DNA-targeting part of the system can operate independently.
Removing the cutting Cas9 function allows CRISPR to be used to target and perform other manipulations on genetic material while leaving the underlying DNA sequence unchanged.
“The real power of CRISPR technology is in its ability to be targeted to specific sites in the 3 billion DNA base pairs that make up our genome,” said Gersbach. “Since we wanted to activate specific genes – rather than change their sequence – we inactivated the DNA-cutting function of the Cas9 protein in CRISPR and used it only to find and bind to the PWS locus. By attaching epigenome-modifying components to this inactivated Cas9, we could localize their activity – such as removal of DNA methylation – to that position in the genome.”
The researchers screened thousands of genomic targets for responses to epigenetic changes that might affect the whole chromosomal region, which revealed a master epigenetic switch for the entire genomic region being silenced.
“We used two distinct methods of reversing imprinting modifications and tested them at thousands of positions around the imprinted genes affected in PWS and found very specific regions that we could modify to activate those genes,” Gersbach detailed. “In particular, removing DNA methylation – a specific chemical modification used in imprinting – led to durable activation of the genes. Moreover, targeting one specific region – called the imprinting center – led to the activation of all genes in the locus.”
Gersbach and team found that using CRISPR as a transient exposure could lead to a permanent, stable effect. This finding leads to the hope of translating this into a durable therapy for PWS patients but also other rare genetic diseases occurring by similar mechanisms.
Looking to make hope a reality
There is still much research to be done before this hope becomes a reality.
“Currently the major obstacle to these types of therapies is ensuring safe and efficient delivery to the affected cells and tissues,” Gersbach explained.
“Many delivery strategies are being investigated, which can largely be classified as viral or non-viral approaches. The non-viral approaches have advantages concerning ease and cost of production but are still in development for achieving broad distribution to certain tissues like the brain, which is most relevant to PWS,” he continued.
To work in human patients, the CRISPR demethylation system would need to be delivered to their neurons across large brain regions, in addition to the epigenetic changes needing to take root and remain stable in already mature neuronal cells.
Gersbach detailed: “Our current work is focused on showing similar results by directly treating neurons, in addition to the stem cells used in this study, as well as demonstrating efficacy in mouse models of the disorder.”
“Many of the drugs in development are focused on addressing specific symptoms of the disease, but this approach is exciting in that it addresses the underlying cause – loss of the genes encoded in the PWS locus,” Gersbach concluded.
Reference: Rohm D, Black JB, McCutcheon SR, et al. Activation of the imprinted Prader-Willi syndrome locus by CRISPR-based epigenome editing. Cell Genomics. 2025;5(2). doi: 10.1016/j.xgen.2025.100770
About the interviewee
Dr. Charles Gersbach is the John W. Strohbehn Distinguished Professor of Biomedical Engineering at Duke University and the director of the Duke Center for Advanced Genomic Technologies. His research interests are genome and epigenome editing, gene therapy, regenerative medicine, biomolecular and cellular engineering, synthetic biology and genomics.
Gersbach’s work has led to new approaches to studying genome structure and function, programming cell biology and treating genetic disease. His work has been recognized through awards including the NIH Director’s New Innovator Award, the NSF CAREER Award, the Outstanding New Investigator Award from the American Society of Gene and Cell Therapy and induction as a Fellow of the American Institute for Medical and Biological Engineering and member of the National Academy of Inventors. He is also the co-founder of several biotechnology companies and an advisor to others.
