A nasal spray treatment for Prader Willi Syndrome

Symptoms such as obsessions, overeating, rage attacks, skin picking, irregular sleep breathing and temperature control,and impairments in learning and understanding social cues are often present in Prader Willi Syndrome (PWS). Brain studies suggest that such symptoms are related to a lack of oxytocin, a natural occurring hormone released from the hypothalamus part of the brain. Syntoncinin-spray (oxytocin) is a synthetic version of this hormone found naturally in the body.  It has been found to be associated with pair bonding, maternal care, sexual behaviour and social attachment in humans.  

A reduction in the number of neurons that produce oxytocin and reduced oxytocin receptor (OTR) gene expression in PWS are believed to play a role in PWS psychopathology. It is suggested the disruption of oxytocin feedback in the hypothalamic paraventricular nucleus possibly influences vasopressin (AVP) signalling (another, related hypothalamic hormone). Use of OT as a therapy for improving behaviours is being actively studied in PWS and other conditions where altered OT pathways are associated with behaviour, such as autism spectrum disorder (ASD), Fragile X and Williams syndrome.
Its potential as a treatment for PWS has generated much interest in the PWS community and some NZ families are specifically raising funds towards the upcoming phase 2 oxytocin study by Drs. Jennifer Miller and Dan Driscoll at the University of Florida.
There have been 2 previous clinical trials of intranasal oxytocin in PWS with conflicting results. The first, a pilot study by Dr. Tauber in France, trialled a single oxytocin dose in a small group of adults and observed a significant increase in trust and decreased sadness tendencies with less disruptive behaviour after 2 days. Hopes were raised that oxytocin may improve socialisation in PWS and longer term and dose-effect studies were recommended. A second study by Dr. Stewart Einfeld at The University of Sydney looked at longer term treatment in adolescents and young adults. 30 families took part in this trial (including some from New Zealand), but the results found that oxytocin had little impact on any measure (behaviour, OCD tendencies, hyperphagia and sleepiness). An increase in temper outbursts was also observed with higher dose oxytocin.
Researchers have remained optimistic because oxytocin signalling is very complex and it is believed that finding the correct formulation and dose may be crucial to the success of oxytocin therapy. Results of the phase 1 study which trialled OT in 24 children 5-11 years at The University of Florida are not yet published, but preliminary anecdotes are extremely promising. Progress is being made toward a phase 2 study due to start soon.
Meanwhile, a similar phase 2 study trialling intranasal OT in children and adolescents (5-18) is being conducted by Dr Eric Hollander and his team at The Albert Einstein College of Medicine in New York. This trial was funded some time ago but has taken a while to get off the ground. Both trials are looking at appetite, behaviours, dose and any side effects.  A third phase 2 trial (sponsored by Ferring Pharmaceuticals) evaluated intranasal OT in a larger group of children and adolescents (10-18) and has been completed. The results of this trial have not yet been published but they are eagerly anticipated as a slightly different form of OT was used (FE992097) to specifically target only the OT receptor which may reduce impact on other systems, i.e. AVP signalling. In comparison, initial studies by Drs.Tauber(2011) and Einfeld(2014) used Syntocinon, a synthetic substance identical to natural oxytocin.
These 3 trials running concurrently will help provide more answers about the most effective use of oxytocin in children with PWS, and if benefit is clearly proven, multiple trials confirming this will help support approval (and the subsequent funding) of oxytocin for PWS in New Zealand.
In 2015, FPWR funded further oxytocin research by Dr. Stewart Einfeld's team in Sydney. One study aims to understand the true nature of the oxytocin abnormality associated with PWS which will help direct oxytocin or vasopressin interventions. They intend to discover if there are similarities with the reduced levels of 9-amino-acid active oxytocin and increased extended oxytocin found to be present in people with ASD. They also intend to find out more about the hypothesised suppressed oxytocin receptor which could make the OT system inactive, even when high levels of OT are administered. It's possible that vasopressin receptors may be responding to administered oxytocin so they will measure plasma levels of the two forms of oxytocin vasopressin and DNA levels of the oxytocin gene. A second study will investigate potential respiratory sinus arrhythmia abnormalities in PWS and how they may relate to emotional and behavioural problems and oxytocin / vasopressin abnormalities. You can read more about these studies here
FPWR also continue to support Dr. Tauber and her team in France who are expanding their initial OT trial in adults for a longer duration trial with multiple doses and using advanced brain imaging analysis. They aim to find the optimal schedule and dose for adults with PWS.
There is still much to learn about the impact of the OT system on the developing brain in PWS. Research in Europe has focused on early alterations from birth in the OT system and pathways of OT receptors in the perinatal period. Last year, a French research team lead by Dr. Meziane published results of a study examining the OT system in mice deficient in Magel2 genes (deficient genes associated with both PWS and autism, causing deficits in social recognition, interaction and a reduced learning ability) and found modifications of the OT system that change from birth to adulthood. Daily administration of OT in the first postnatal week was sufficient to prevent deficits in social behaviour and learning abilities in adult males,‚Äč and partly restore a normal OT system.
FPWR have funded a study this year by Dr. Muscatelli to further understand the relationship between the inactivation of Magel2 and the alteration of the OT system and to investigate how an administration of oxytocin acts during brain development to allow a long term effect in Magel 2 deficient mice. This study will increase knowledge about adequate supplemental therapy in infancy and provide insight into effective OT administration at different points of the OT system maturation (infancy to adulthood).
Also, eagerly awaited are the outcomes of a recently completed study by Dr Tauber's team at University Hospital in Toulouse which examined the tolerance of a repeated OT dose in infants less than 5 months.

It is hoped that the combined knowledge gained from these past and ongoing trials will refine understanding of the potential of oxytocin therapy and accelerate its availability as a treatment for PWS.