In this 50-minute video, Theresa Strong and other FPWR research team members sum up the presentations given at the 2019 PWS Research Symposium. This overview provides a great synopsis of PWS research developments and work in progress, including PWS genetic therapy research, caring for people with PWS, managing clinical complications, newborn screening, drug development, pretend play, the PWS weight study, the Global PWS Registry, and clinical trials. Click below to watch the video. If you're short on time, scroll down for time stamps to find the portions you're most interested in.
Presentation Summary With Timestamps
0:00 Introduction - Who is Theresa Strong?
5:35 International PWS Clinical Trials Consortium
- Purpose, members, mission
- Current work:
- Support/Develop clinical trial endpoints
- Incorporate patient and caregiver perspectives and benefit/risk assessment
- PWS Across the Lifespan [videos] (5min and 20 min versions, pwsctc.org)
- Caregiver burden in PWS (2018 publication)
- Caregiver treatment priorities and benefit/risk assessment (2018 publication)
- Patient preferences
- Critical Path Innovation meeting with FDA (2018)
- Upcoming work:
- Supporting patient access of FDA approved therapies
15:00 PWS Genetic Therapy Workshop
- Workshop brought together experts to discuss challenges and promise of genetic therapy for PWS
- Big Questions: All subtypes of PWS have genes present but silent – can we turn them on or replace them? What do we need to do to determine feasibility? How can we advance genetic therapy for PWS as efficiently as possible?
15:07 Research Symposium Overview
- Day and a half event: 26 oral presentations + 19 poster presentations
- 150 attendees from around the world (Australia, US, Canada, Israel, Chile, Spain)
- Outstanding science! Excellent, challenging questions and collaborative environment
- Broad topics of investigation from genetics to rug development to clinical care
- Interaction of industry, basic scientists, clinicians and family/community members
22:45 PWS Genetics
- It’s a very complex region involved in PWS including multiple genes & SNORD RNAs
- Many studies we fund are looking to see what the PWS genes do and what happens in the cell when they are inactive. This is important to know in order to find drugs that may improve symptoms of PWS.
- SNORD116 – everyone with PWS is missing SNORD116
- MAGEL2 – lost in almost all people with PWS and when mutated is the cause of SYS
25:22 What is the normal function of the PWS region genes? SNORD116
- LaSalle – SNORD116 is important in circadian rhythm. (People with PWS have an atypical sleep/wake cycle). LaSalle has discovered an “RNA cloud”, generated by the RNA from the SNORD116 region, may be important for regulating circadian rhythm
- Stamm – investigating how SNORD116 affects other RNAs in the cell - using stem cells (derived from donated PWS baby teeth)
27:16 What is the normal function of the PWS region genes? MAGEL2
- Wevrick – what protiens does Magel2 interact with?
- Chen – when you lose MAGEL2, other proteins don’t recycle like they are supposed to… this could be something we can screen drugs for to see if we can correct the defect.
28:20 Understanding the underlying molecular deficits in PWS
- Chung – what are the RNA differences in PWS cells compared to cells from typically developing individuals?
- Reiter – what is the underlying cause of differences between genetic subtypes of PWS? Why do individuals with PWS via UPD have a higher risk of autism?
29:17 Steps to Genetic Therapy for PWS
- Chamberlain – Epigenetic regulation of the maternal allele
- Matharu – CRISPR activation: A therapeutic strategy for diseases where gene expression needs to be ‘turned up’ .
- Blewett – Developing a novel gene therapy method for PWS. SMCHD1 is an epigenetic regulator strictly required to establish and maintain imprinting at Magel2, Ndn and Mkrn3 in the PWS cluster
30:38 Caring for Individuals with PWS
- Stafford – US prevalence of PWS, mortality and comparative comorbidity of patients. 9000 patients in U.S. found. Increased risk of diabetes early in life (assumed with obesity). Increased mortality (3-fold) was seen across the lifespan.
- McTighe – Outpatient based program opening at Children’s Institute of Pittsburgh.
32:43 Managing Clinical Complication of PWS
- Baraghithy - Underlying cause of osteoporosis in PWS. Fractures and breaks are more common in people with PWS. Potential therapeutic identified.
33:30 Newborn Screen for PWS
- Godler - funded by FPWR, Angelman Syndrome Foundation and the Australian government, has developed a newborn screen for the three disorders. Screen tests blood from the heel prick for EVERY newborn, which will cost less than $2 per disorder. Working to pilot in US. If adopted, the screen will give us the true incidence of PWS and allow all babies to be diagnosed immediately after they are born.
35:35 Drug Development
- A previous drug in clinical trial many years ago was very effective on weight loss, but had psychiatric side effects. Now we are investigating a next generation compound (CBR1 blocker) with the same metabolic benefits, without the psychiatric effects. FPWR is supporting this company to help move drug into clinical trials. Goal: Phase 1 in 2020, then in PWS after that.
37:09 Pretend Play
- Kids with PWS don’t play the same as typical children. A telehealth pilot study to improve play in kids has shown play can be improved with intervention. Now working to see if these improvements cross over into general development
38:05 PWS Weight Study
- Followed 165 individuals, ages 12+ for 6 months. Showed how weight in people with PWS changes over time. Weight is generally stable but there is great variability. People on GH for a longer period of time generally had lower weights and BMI’s than those not on GH.
39:34 FPWR is developing tools to facilitate research across the drug discovery development pathway
- The Global PWS Registry is very valuable to research and is an easy (and important) way every family can get involved in research.
- Several studies were presented using data from the registry:
- Psychiatric medication usages in patients with PWS (Pachkowski, Soleno Therapeutcis)
- Common behaviors in PWS patients (Vissapragada, Soleno Therapeutics)
- PATH for PWS: a natural history study of serous medical events (Matesevac, FPWR)
40:28 PWS Clinical Trial Presentations
- FPWR - Guanfacine
- Millendo – Zephyr - Livoletide
- Harmony Biosciences – Pitolisant
- Soleno Therapeutics – Destiny PWS – DCCR