New research for 2017—made possible by YOU!

Pre-clinical assessment of cannabidiol as a treatment for Angelman syndrome

Paul Carney, M.D., UNC-Chapel Hill

Summary of Dr. Carney Study

A national figure in cannabidiol (CBD) research, Dr. Paul Carney has been working with the National Academy of Medicine, the National Institute of Drug Abuse and the Florida Department of Health for several years to evaluate existing research on CBD and its potential therapeutic effects. Existing research is anecdotal and there is little, if any, scientific research proving how CBD works; however, some clinicians have already begun using it in a clinical setting. It is known that CBD could be a powerful drug to address symptoms of Angelman syndrome such as seizures, behavioral and motor challenges, and others—but no scientific research exists to support it. Dr. Carney, in collaboration with Dr. Ben Philpot, is pioneering this research to evaluate its effectiveness in treating symptoms of Angelman syndrome.

Dr. Carney will be testing CBD in an AS mouse model for its effectiveness in specific areas: behavioral and motor deficits, seizures and brain activity. This is the first pre-clinical evaluation of CBD in Angelman syndrome, a necessary step to justify a clinical trial per the NIH’s standards.

“Dr. Carney’s research will be valuable to the Angelman syndrome community. Currently, many families are obtaining CBD through hemp oil or from medical marijuana. These formulations differ from each other and can vary significantly among manufacturers. Many families have reported that it has helped with seizures, non-epileptic myoclonus, sleep and even anxiety, but no formal studies have been done in individuals with Angelman syndrome, and in the general population this has only been studied for its effects on seizures. With so many families trying these compounds or interested in trying them, this study will be useful in developing parameters for future clinical trials.”

-Dr. Ron Thibert, M.D. and AS Clinician at the AS Clinic at Massachusetts General Hospital in Boston

Pilot study to validate three novel classes of small molecules to unsilence paternal Ube3a allele

Ben Philpot, Ph.D., UNC-Chapel Hill

Summary of Dr. Philpot Study

Dr. Ben Philpot is examining three new potential drugs for their ability to unsilence the paternal copy of Ube3a. These drugs were identified using the same approach Dr. Philpot previously used to identify topoisomerase inhibitors as potential therapeutics for Angelman syndrome.  The potential clinical use of topoisomerase inhibitors is still being pursued by Dr. Philpot and various pharmaceutical companies. Not one to rest on his previous laurels, Dr. Philpot is now examining three new compounds that may achieve the same effect through different mechanisms.

Dr. Philpot’s goal is to determine if these new drugs can unsilence paternal Ube3a in an AS mouse model and if they can be safely administered. He will be evaluating the mechanism by which they act, the potential side effects, how well the drugs penetrate the brain, and the optimal method of delivering the drugs to the brain. This work focuses on developing these drugs as potential therapeutic approaches to cure AS.

The testing of these new compounds originated out of research conducted in partnership with Dr. Philpot and Pfizer, Inc.

Gene Therapy in Angelman Syndrome

Steven Gray, Ph.D., University of Texas Southwestern Medical Center

Gene therapy expert Dr. Steven Gray explains his ASF-funded research on gene therapy in Angelman syndrome.

Summary of Dr. Gray study.

Dr. Steven Gray is applying his years of experience using gene therapy as a treatment for Giant Axonal Neuropathy (GAN), Rett syndrome, and several other neurological disorders to Angelman syndrome. Dr. Gray has been a pioneer in the field of developing AAV (adeno-associated virus) vectors to inject into the spinal fluid, a strategy that is being used to treat several neurogenetic disorders. Dr. Gray also has specific experience in translating gene therapy treatments from lab testing into human testing. He led the development of the first delivery of a viral gene therapy vector injected into the spinal fluid of humans. Thus, he has a toolkit of knowledge to navigate any unknown challenges that may arise in applying gene therapy to Angelman syndrome.

Dr. Gray’s overall strategy is first envisioning how a human treatment would be administered and dosed, and then scale that back to lab studies to directly model how they envision the treatment in humans. Dr. Gray is taking an aggressive approach: deliver AAV vectors in high doses in AS-mice lab studies to determine the “best- and worst-case scenario” upper bar for treatment. If that proves safe, then it provides latitude to move towards a human treatment much more quickly. If it is not safe, then the approach can be scaled back and/or redesigned. The research team anticipates the possibility of UBE3A gene therapy complications due to experience with some other disorders such as Rett syndrome, so the initial priority is to determine how safe or unsafe this gene therapy approach may be. This will provide a guide for gene therapy in Angelman syndrome for future studies and treatments with the ultimate goal of accelerating a cure for Angelman syndrome.

Pathophysiological impact of diverse deregulation of tonic inhibition in Angelman syndrome

Dr. Kiyoshi Egawa – Hokkaido University Graduate School of Medicine, Japan

Dr. Kiyoshi Egawa from the Hokkaido University Graduate School of Medicine in Japan is conducting further research on Gaboxadol’s potential therapeutic affects in other parts of the AS brain, helping guide current and future clinical trials and move us closer to a cure.

AS research expert Dr. Ben Philpot says that “it’s critically important to do these types of pre-clinical studies to guide ongoing therapies and therapeutic trials. The hope is these additional studies, such as Dr. Egawa’s, will provide feedback so even better therapeutics are designed in the future.”

The ASF has funded two groundbreaking communications studies this year, each taking a unique approach to helping individuals with AS—no matter where they are on the communications spectrum—to better communicate their desires and needs.  

Speech generating devices in children
with Angelman syndrome: An effectiveness trial

Dr. Anjali Sadhwani – Boston Children’s Hospital

Augmentative and Alternative Communication Immersion Project for Individuals with Angelman Syndrome

Dr. Samuel Sennott – Portland State University

Summary of Dr. Sadhwani study.

The overall goal of this study is to improve the day-to-day functioning of children with AS by teaching them how to influence their environment and the people they interact with. A major component of this is helping them to better communicate their needs and desires. This study targets beginning communicators, a smaller population of people in the AS community who are not yet effectively using technology or a system—such as an iPad app or other augmentative and alternative communication (AAC) devices—to communicate.

To identify children for the study, the parents and caregivers (including teachers or speech and language pathologist) of beginning communicators will complete a questionnaire about the child to help determine where the child’s current communication skills stand. Once children who are eligible for the study have been identified, the study will begin with a psychologist evaluating the child’s general development, motor and language skills. An AAC evaluation will then be performed by a speech and language pathologist to determine potentially beneficial AAC applications or devices to support communication. These evaluations incorporate the Communications Matrix, which is a proven method for the evaluation of communication skills.

Following these evaluations, the research team will seek input from the child’s parents to determine the AAC device or app that best fits their child’s communication needs. For the following 12 weeks, graduate students in Communication Sciences and Disorders from Northeastern University will visit each child in his/her home or school twice-per-week to teach the child how to use the device.

Should our intervention be effective we anticipate that, by the end of the 12 weeks, beginning communicators will begin to learn how to use the device through this home-based intervention. One month later, the graduate students will visit the child to ensure the device remains effective in communicating his or her respective needs.

We plan to enroll up to 15 children with AS. The goal of this study is to:

  • Help individuals with AS who are earlier, emerging communicators make significant gains in the direction of more effective communication skills.
  • Establish a program that has shown success in improving communication in certain individuals with AS.

Summary of Dr. Sennott study.

Language allows us to share what matters to us with the people we care most about. Individuals with AS face major barriers to access language. Typically developing children learn to use speech to communicate only after thousands of hours of watching and hearing others using speech. This immersion in our native language is important to our language development. Anyone who has tried to learn a second language by only taking lessons knows how difficult it is to learn a language in the absence of immersion with others using the language. However, individuals with AS rarely witness others communicating in a method that they, too, can use. Research tells us that learning to use an alternative communication system (AAC), where we touch a photo or symbol to express a word, requires the same kind of immersion in the language that it takes to learn a second language. Supporting communication in individuals with AS requires creating an immersive language experience with the student’s AAC. This study aims to teach parents and other communication partners to use the student’s AAC as their own voice in order to provide this immersion.

The purpose of this study is to test a research-based training program specific to AS that has proven success with other populations who have a disability and cannot use speech. This study teaches the people who live with, learn with, and support the individual with AS on a regular basis to be better communication partners ourselves, by modeling use of AAC in our ordinary communication with each other and with the individual with AS. Measurement and reporting during the study will evaluate the effectiveness of the program to see A) if communication partners learned new skills using the AAC device, and B) if the individual with AS developed new communication skills. The goal of the study is to create a successful communication training program that families of individuals with AS can replicate at home, school, and wherever their individual with AS spends most of their time.

The study will begin with researchers and the individual’s communication partners—parents and educators, and others who interact regularly with the individual with AS—discussing how the individual communicates currently, what AAC device is available, their interests, and so on. Communication partners will then receive coaching based on the “Model, Encourage, Respond” strategy. The following example might happen during mealtime.

  • Model: communication partner asks a question, using the communication device to state the words in bold: “What would you LIKE to EAT?”
  • Encourage: communication partner pauses and looks expectantly to the individual with AS for a response, giving him/her at least 5 seconds to respond.
  • Respond: individual with AS responds by reaching for a food. Communication partner uses the communication device to say: “Applesauce! I LIKE applesauce too.”

This example might happen in the evening when the family is relaxed at home.

  • Model: communication partner asks a question, using the communication device to state the words in bold: “Hmm. I WANT to watch TV. WHAT should we watch?”
  • Encourage: communication partner pauses and looks to the individual with AS for a response.
  • Respond: individual with AS picks up the DVD case for Harry Potter. Communication partner responds by using the communication device to say: “Good idea! Harry Potter! I LIKE Harry Potter, too. Let’s WATCH Harry Potter!”

This example might occur on the weekend.

  • Model: communication partner asks a question, using the communication device to state the words in bold: “WHAT should DO this weekend?“
  • Encourage: communication partner pauses and looks to the individual with AS for a response, waiting several seconds for a response.
  • Respond: individual with AS does not respond. Communication partner says “I want to GO somewhere” and navigates to PLACES in the communication system, then says “Maybe we should GO to the PARK…or maybe we should GO to the MALL…” Communication partner pauses again. Individual with AS indicates Pizza Hut on the communication device. Communication partner responds “Oh! You want to GO out to EAT at PIZZA HUT! We could DO

This strategy creates a natural back-and-forth conversation between the communication partner and individual with AS that, over time, could improve the quality of the interaction and improve use of AAC devices. Research with other individuals with communication disabilities indicates that this approach improves the individual’s ability to:

  • recognize visual symbols
  • find symbols in a AAC device
  • use symbols to express messages
  • respond and maintain a communication interaction
  • combine symbols to express more complex messages
  • participate and interact at home, school and in the community.

The idea seems very basic, but since no studies specific to Angelman syndrome have been conducted, this communication partner training strategy will help gather tangible scientific data to eventually provide families with the most effective communication training in the future.

The ultimate goal is that everyone in the individual’s life will be involved with the program. This helps the individual with AS progressively improve his/her use of the communication device by observing others using the AAC device in meaningful experiences throughout the day.