Promising First Steps Towards Genetic Therapy for Prader-Willi Syndrome

Genetic or “epigenetic”* strategies to treat PWS are attractive because they aim to directly correct the underlying issue in PWS – the lack of expression of PWS-region genes. All individuals with PWS have at least one copy of the PWS genes present, but silent, on their maternally-inherited chromosome 15 — those with PWS by deletion have one maternal chromosome 15, while those with UPD have two maternal 15s. Activating expression of the PWS genes on those maternal chromosomes has the potential to restore normal cell function, and might improve the clinical characteristics of PWS. Current genetic strategies for PWS, several of which are supported by FPWR, are examining how best to “activate” the PWS genes that each person with PWS has. Dr. Yong-hui Jiang of Duke University has taken a major step towards developing a genetic therapy for PWS, as reported today in the high profile journal, Nature Medicine: Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome

Those of you who have been supporting FPWR for a couple years may remember that Dr. Jiang was the recipient of funding through the PWS “Puzzle Project” funding in 2014 (thank you to all those donors — this study is a direct result of those donations!). With that funding, Dr. Jiang’s lab screened thousands and thousands of drug compounds, seeking out small molecules that could ‘activate’ PWS gene expression in a cells derived from PWS mice. As reported in this new paper, he found two compounds that seemed to do so with high efficiency – UNC0638 and UNC0642. When added to PWS cells, even at low concentrations, these drugs caused the PWS region genes on the maternal chromosome to become active and express the PWS genes. The authors then tested the compounds in skin cells from a person with PWS via the typical large deletion. Here, too, they showed that UNC0638 and 0642 activated PWS-region gene expression from the maternal chromosome 15, including expression of the important SNORD116 gene cluster and the protein coding Necdin gene, in the cells. The drugs were able to restore gene expression to ~30% of normal.

Dr. Jiang then asked what would happen if these compounds were given to a mouse with PWS. There are many different models of PWS, and these mimic the initial “failure to thrive” stage in humans with varying severity. The PWS deletion mouse model that Dr. Jiang used is among the most severe with respect to this characteristic; all of the affected mice show significant feeding problems and the newborn mice almost all die by 14 days old; the ~5%  of surviving mice show severely stunted growth. Dr. Jiang treated these PWS mice with UNC0642 drug because this compound had previously been characterized and found to have low toxicity, good brain penetration, and high potency. When treated daily for 5 days during the second week of life (they are too fragile to handle in the first week), the PWS mice showed improved survival, with the majority living past 2 weeks, and about 15% surviving long term, with improved growth and weight gain, and normal appearance and activity compared to the untreated mice. These mice also showed expression of the PWS genes Snrpn and Snord116 in their brains, demonstrating that UNC0642 had the expected effect on gene expression. Importantly, treating normal mice with UNC0642 did not cause any harmful effects in an initial screen of toxicity. The authors also found that expression of Ube3a, which normally occurs from the maternal chromosome, didn’t appear to be changed by expression of the PWS genes. This is important because one wouldn’t want a PWS genetic therapy to decrease Ube3a expression, as loss of Ube3a expression causes Angelman syndrome.

Here’s a bit more detail for those interested in mechanism – it’s perhaps a bit surprising that the UNC0638 and 0642 compounds didn’t actually alter the DNA in the PWS region. DNA is typically ‘silenced’ by the addition of methyl groups directly to the DNA. Thus, one might expect that the drugs would have to remove the DNA methyl groups to activate the genes. In fact, the authors use a series of molecular studies to show that the drugs only needed to modify the proteins that the DNA wraps around (the histones) to get the genes to activate. UNC0638 and 0642 are known to be selective inhibitors of G9a, a protein that methylates lysine 9 of the histone H3 protein (H3K9). Apparently, changing the characteristics of the H3 histone protein is sufficient to allow activation and expression of the associated genetic material (the PWS genes), suggesting a critical role for histone modification in controlling gene expression in the region. This somewhat surprising finding speaks to the power of using an unbiased, high throughput screen for gene activation.

This work encompasses several important advances with respect to genetic therapy for PWS. First, it establishes proof of concept that a drug can cross the blood brain barrier, enter neurons and alter the ‘silent’ maternal chromosome to activate expression of the critical PWS genes. Second, it shows that expression of these genes in newborn PWS mice has a significant impact on clinical characteristics, in this case, survival. (because this mouse model normally does not live, we don’t know whether it exhibits hyperphagia or not, and if the drug would impact that characteristic). Third, it defines the particular epigenetic modifiers (histone methyl transferases) that are critical to regulating gene expression in the PWS region of chromosome 15. Fourth, the drug provides a means to ask important general feasibility questions about gene activation therapy for PWS – when, where, how much, at what point during development does such a drug need to be given, how does genetic therapy of deletion vs. UPD differ, etc.

Finally, as per the authors: “Our study provides a critical step toward the development of a specific molecular therapy for human PWS. Based on these promising results, comprehensive evaluation of the efficacy and tolerability of G9a inhibitors in preclinical studies is warranted to fully explore therapeutic potential of G9a inhibitors for treating PWS.” Additional ‘preclinical’ studies are needed (thus our new support for Dr. Jiang in 2016 to move that forward), but it’s possible that these specific compounds, or new compounds derived from them, could be tested in humans with PWS sometime in the not so distant future.

With these drugs, the PWS research community has new insight and important tools to vigorously pursue the promise of genetic therapy for PWS. We’re thrilled at this progress and look forward to continuing to support Dr. Jiang and the other scientists pursuing genetic therapy for PWS, a major program of FPWR's 5 year research plan.


[*”genetic” refers to the DNA, while “epigenetic” refers to chemical modifications of the DNA and associated proteins (histones)]


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Theresa Strong


Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.