Targeting SMCHD1 to address the underlying cause of PWS and SYS

Funding Summary

Associate Professor Blewitt and her research team study how genes shift between ‘sleeping’ to ‘awake’ states, and how this impacts a range of diseases.  “A protein called SMCHD1 keeps many genes in their sleeping state,” Associate Professor Blewitt said. “We discovered that SMCHD1’s targets include some of the maternal genes that are involved in Prader-Willi syndrome. We have already discovered that if the function of SMCHD1 is blocked, these genes will wake up and become functional.” 

Funding from FPWR and the Prader-Willi Research Foundation of Australia will allow Professor Blewitt's team to develop the necessary tools, and to test if removing SMCHD1 in patient cells (PWS and SYS) will allow the PWS genes to become active. This study is a proof-of-concept study for a potential genetic therapy for PWS and SYS. You can learn more about this study in this video below highlighting Dr. Blewitt's work or read this short article: "Waking 'sleeping genes' could help Prader-Willi syndrome"




Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.


Watch the full webinar describing the 8 research projects funded in this grant cycle here. 


Lay Abstract

Prader-Willi syndrome (PWS) is caused by lack of expression of a cluster of genes normally expressed only from the copy you inherit from your father; the copy from your mother is switched off. PWS occurs essentially because the copy from the father is absent, but as in people without disease, the maternal copy is switched off. Schaaf-Yang syndrome (SYS) is very similar but relates to only one gene in this cluster, rather than several genes. Therefore, a potential therapy for both diseases is to awaken the maternal copy of these genes by inhibiting factors that normally silence these genes on the maternal copy. SMCHD1 is one such factor, that we discovered 10 years ago, and have since shown in mouse models functions to switch off the PWS cluster of genes. Thus, inhibiting SMCHD1 is a potential new treatment for PWS and SYS. Importantly, targeting SMCHD1 would treat the cause of PWS and SYS, and thus have the best chance of most effectively treating the wide array of symptoms experienced by patients, unlike any current treatment.

Our data in mice provides excellent baseline evidence that it will work in humans. However, to move this project forward, we wish to address if see activation of PWS genes in patient-derived cells, specifically the cells of origin of the disease, neurons from the hypothalamus of the brain. It is impossible to sample hypothalamic brain cells. Instead, we will use cells derived from PWS and SYS patient cells that have the capacity to make any cell in the body. We will use these cells to produce hypothalamic neurons, and test whether SMCHD1 removal results in activation of PWS genes from the maternal copy. This will provide vital proof-of-concept data in human patient-derived cells, to take SMCHD1 forward as a valid drug target in PWS and SYS.

Should our project prove successful, we would seek to develop the set of compounds we have that inhibit SMCHD1 function, into safe medicines for patients. We are the only group worldwide to have such compounds, so we are well-placed to advance these findings to the clinic. We would also seek to use animal studies to test whether SMCHD1 deletion or inhibition has therapeutic benefit in terms of the symptoms that can be modelled in such studies. The experiments described here lay the foundation for therapeutic inhibition of SMCHD1; they provide the critical proof-of-concept data required for investment from Pharmaceutical companies.

Research Outcomes: Public Summary

In this research we have studied the role of SMCHD1 at the human Prader Willi syndrome (PWS) locus of genes, with the hope of learning whether SMCHD1 is a relevant target for new therapies for PWS patients. In model organisms we found that removing SMCHD1 results in the maternal imprinted copy of some Prader Willi locus genes, namely Magel2, Ndn and Mkrn3, are switched on to some extent. Here, we used neural progenitor cells derived from PWS patient-derived induced pluripotent cells, as these are a relevant cell type when considering patient treatment. We have found that when SMCHD1 function is disrupted in PWS patient-derived neural lineage cells, there is a small increase in expression of PWS locus genes from the normally imprinted maternal copy of the genes. The level of reactivation is small, suggesting that there is more that we need to learn about how SMCHD1 works at this locus. Overall, our data suggest that SMCHD1 does play a role in switching off the PWS locus genes in humans as it does in model systems. This provides preliminary promising data for future proof-of-concept work on SMCHD1 as a new therapeutic target in PWS.

Research Outcomes: Additional Funding

Dr. Blewitt recently received funding from the National Drug Discovery Centre to fast track a screen for treatments for PWS. Prader Willi Syndrome (PWS) is a debilitating, incurable disease apparent from birth, with devastating consequences for patients and their families. Current treatments only target the symptoms of this complex disease, none address the root cause. Importantly, no treatments target the developmental delay or hypotonia suffered by all patients from birth, leaving a large unmet clinical need for PWS sufferers. Here we seek to rectify this situation, by screening >300,000 compounds to identify those that have the potential to treat the underlying cause of PWS. Our target is unique and may also be relevant to other diseases that similarly lack targeted treatments. For more information about this award, click here.

Funded Year:


Awarded to:

Marnie Blewitt, Ph.D




Walter & Eliza Hall Inst of Medical Research


Marnie Blewitt, Ph.D

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