Angelman Syndrome Research Funded in 2018

Newborn Screening for Angelman syndrome, Prader-Willi, Fragile X and Dup15q Syndromes

David Godler, PhD
Murdoch Children’s Research Institute in Melbourne, Australia

Summary of Dr. Godler Study

In a pilot study, Associate Professor David Godler from the Murdoch Children’s Research Institute in Melbourne, Australia, will screen 75,000 newborns, establishing the feasibility of the test for large-scale screening.

“Newborn screening means families with loved ones with Angelman, Prader-Willi, Fragile X and Dup15q syndromes find a diagnosis in weeks instead of years, avoiding a painful diagnostic journey. And, if we can diagnose individuals earlier, we have the best chance of reversing the effects and improving their quality of life much sooner,” says Eileen Braun, Executive Director of the Angelman Syndrome Foundation and mother to a young woman with Angelman syndrome (AS). “Research, including studies funded by the ASF, is moving quickly toward therapeutics and a cure for AS, and experts are now pinpointing the optimal window for applying a cure. The sooner we can diagnose, the sooner we can apply life-changing treatments.”

“Having a cost-effective test to accurately diagnose these syndromes in the newborn period is key to ensuring that families receive optimal medical care and support,” adds Theresa Strong, Director of Research Programs for FPWR. “The study will validate the newborn screening tool so that, once approved for use, it can be used to screen all babies in the newborn period.”

“This would allow individuals to have standard-of-care therapies right from the beginning,” says Dr. Jessica Duis, MD, MS, Director of the Comprehensive Angelman Syndrome and Prader-Willi Clinics at Vanderbilt University Medical Center. “For example, for Prader-Willi Syndrome (PWS), this means growth hormones and early intervention therapies that we know from experience have huge benefits.”

When available, life-changing therapeutics and a cure for AS could be implemented within the first weeks of life.

Current rates of incidence of PWS and AS vary widely from 1:12,000 and 1:30,000 live births. The study will also help understand the true incidence and full spectrum of these disorders in the population. 

AS in particular is often not diagnosed until individuals are between one to three years of age and delays are noted, significantly delaying therapies and creating stress and hardship for families.

Validation of therapeutic guide RNAs targeting the UBE3A antisense transcript

Mark Zylka, PhD
UNC Chapel Hill

Summary of Dr. Zylka Study

Dr. Zylka’s lab and others have been exploring the possibility that symptoms associated with Angelman syndrome (AS) can be treated by unsilencing the paternal copy of Ube3a. Dr. Zylka’s lab recently found that paternal Ube3a can be unsilenced in neurons by topoisomerase inhibitors, a drug compound, which work by interfering with expression of the extremely long Ube3a‐ATS transcript. In addition, AS research in other labs found that targeting the Ube3a‐ATS with antisense oligonucleotides (ASOs) can also unsilence paternal Ube3a. While both of these approaches have advantages and disadvantages, neither approach has yet been shown to work in individuals with AS. With the advent of CRISPR/Cas9 technology, it is now possible to achieve targeted and permanent deletion of the Ube3a‐ATS in neurons. However, we still do not have a full understanding of which regulatory elements control Ube3a‐ATS expression and function. 

Dr. Zylka will complete a screening a library of guide RNAs (gRNAs) to identify regions in the Ube3a‐ATS that could serve as therapeutic targets in unsilencing paternal UBE3a. Then using mouse models, attempt to unsilence Ube3a using Adeno‐Associated Virus (AAV) particles and rescue AS‐linked behaviors in AS model mice. The ultimate goal of the study is to identify therapeutic gRNAs that permanently unsilence Ube3a‐ATS, and serve as the foundation for a gene therapy for AS.