The science of oxytocin (OT) and its potential therapeutic benefit in PWS continues to be a high profile, priority research area for the PWS community and for FPWR. Several studies have taken place investigating oxytocin as a therapeutic for PWS, however, there is still much more we need to know. There is a lot going on, and that’s very encouraging but, like oxytocin itself, the path is complex.
Some relevant background information on this topic can be found in previous blog posts from 2011 and earlier in 2015, and other resources listed below. Here, we highlight some recent advances in understanding the role of oxytocin in PWS, as well as the current landscape of this important and complicated area of PWS research.
A study of post-mortem brains from individuals with PWS gave the first indication that OT neurons may be reduced in PWS (Swaab, 1995). Complementary studies in mouse models of PWS have helped further define the nature of OT deficits in PWS, and are helping to guide clinical development. The collaborative work of Drs. Muscatelli and Tauber has made significant contributions to this effort. Using a mouse model of PWS that lacks the Magel2 gene, Dr. Muscatelli previously explored the impact of administering OT soon after birth. These mice are born with reduced levels of OT in the hypothalamus region of the brain. They have very weak suckling ability, which leads to poor feeding and a high mortality rate. Those mice that do survive show significant deficits in both social interactions and learning ability. In 2010, Dr. Muscatelli’s group published a paper (Schaller 2010) showing that a single injection of OT within hours of birth rescued the ability of the mice to suckle and led to 100% survival. Now, in follow up work that was just published (Meziane, 2015), the group reports on the long-term effects of early OT treatment. Those PWS mice given OT in the neonatal period show significant improvement of the social and cognitive defects when they reached adulthood. This suggests that OT at birth may play a critical role in setting long-term social cognitive abilities, with treatment shortly after birth possibly having lifelong impacts on these parameters. Dr. Christian Schaaf, an FWPR funded investigator examining the role of Magel2 in autism in PWS, provides a very nice commentary on the article (MAGEL2 and Oxytocin, Implications for Prader-Willi Syndrome and Beyond), including insights on OT studies for patients with PWS, with an emphasis on the need for carefully planned clinical trials given the complexity of potential OT effects.
Dr. Muscatelli continues her work with a current FPWR/Prader-Willl France funded study “How does oxytocin cure early feeding and adult social behavior alterations in Magel2 deficient mice, a model for the PWS?”. This project will connect the dots between the biological effect of the OT treatment and the observed impact on feeding, social behavior, and cognition. Answering these questions will be critical in guiding clinical development of OT as a potential therapy for PWS. For example, the OT system in the brain changes dramatically with development and maturation, so it’s quite possible that OT administration at different times (infancy, childhood, adulthood) will have different long term and short term effects, and that dosing will be critical across the spectrum. The animal models generated from this project will allow the researchers to fully explore these parameters.
In addition to the work in animals, several clinical studies of OT in individuals with PWS are ongoing, have been recently completed, or are planned for the near future. As has been the case for OT clinical studies in other neurodevelopmental disorders, it’s likely that extensive work will have to go into developing an effective treatment regimen. Two recent overviews of OT therapeutic development in general (eg, for autism) provide a backdrop for the PWS-specific studies (see The Hard Science of Oxytocin and Can Oxytocin Treat Autism?)
Building on the mouse studies suggesting that an early OT treatment could be an effective therapeutic approach for PWS, Dr. Tauber’s group is examining the effects of OT treatment in infants with PWS; the outcomes of those initial studies will be available soon. In children and adults with PWS, a few studies have been completed and the results to date are mixed or not yet reported. Dr. Tauber’s initial study in adults (single dose) gave encouraging results (Tauber 2011) and formed the basis for a larger, more extensive study (see below). Dr. Stewart Einfeld from Sydney, Australia performed a Phase 2 placebo controlled, double blind cross-over study of OT in thirty adolescents and young adults with PWS. In that study (Einfeld 2014), no significant improvements in any of the behavior/social measures were seen, and in fact, the higher dose of oxytocin was associated with an increase in temper outbursts. This study points to the complex nature of oxytocin biology, where the concept of ‘less is more’ may be at play, since OT may impact other biological systems (eg, vasopressin). The largest study to date, a Phase 2 study supported by Ferring Pharmaceuticals, investigated the effects of a slightly different form of oxytocin (FE 992097, which may have the advantage of more specifically engaging only the OT receptor) in children and adolescents with PWS. This study has been completed, but the results aren’t yet published. We look forward to those results being reported and to the possibility of this OT drug advancing to pivotal Phase 3 studies.
With each of these studies, the field gains experience in understanding appropriate dosing, how best to measure potential benefits, and what possible side effects might arise. New studies on the horizon will be testing a number of variables including the formulation, dose, optimal age, nutritional phase, genetic subtype and other factors. This includes a longer study of multiple doses in adults, currently ongoing, funded by FPWR in collaboration with Prader Willi France. This study will also specifically explore changes in the brain following oxytocin administration, using advanced brain imaging, and may provide new insights into how OT affects the adult PWS brain. A pending Phase 2a study will focus on the effect of OT on hyperphagia in children with PWS [funded by FPWR in partnership with PWSA(USA) as a “Best Idea Grants (BIG)” and with additional funds from Prader-Willi Angels], and is set to get underway in New York City in early fall 2015 (Hollander). Another FPWR-funded study (to be announced in fall 2015), will bring together world experts in OT biology and PWS to lay important groundwork for fully understanding the nature of OT deficits in children with PWS, and should provide critical information for measuring OT effects in the upcoming trials. A recent buzz has also been generated by Dr. Miller’s ongoing Phase I study of oxytocin in children. This study is not yet complete and unblinded, but there are some encouraging anecdotal reports that have generated excitement in the community. The follow up Phase 2 study is in early development, and will seek to expand the treatment time, participant group size and possibly age range, and may provide an opportunity to gain additional insight into the physiological effects of OT administration in PWS.
Overall, the use of oxytocin as a potential therapy for PWS remains an exciting area of research. The path forward is likely to be a long and may not always be straight-forward, but the aggregate of the studies completed to date plus those planned should lead to a solid understanding the role of OT in PWS therapeutics, including optimal timing, dose, and short and long term effects.