11 May

ASF-funded Research Identifies Biomarker for Clinical Trials

ASF-funded research published in the Journal of Neurodevelopmental Disorders has identified that delta—a frequency of brain rhythms identifiable by EEG scanscan serve as a reliable biomarker for pre-clinical and clinical trials in Angelman syndrome. The research team, led by Dr. Mike Sidorov at the University of North Carolina-Chapel Hill, compared existing EEG data from the Angelman Syndrome Natural History Study to neuro-typical EEG data from Massachusetts General Hospital. The study showed that delta abnormalities can be seen across the brain of children with Angelman syndrome, and during both sleep and wake. 

“We focused on delta because it is the most commonly reported abnormality in AS EEG scans,” said Sidorov. “In doing so, we consistently found that nearly every individual with AS has increased delta compared to neuro-typical individuals.” Most importantly, we found that delta abnormalities can be quantified, said Sidorov. “By reducing delta to a single number, we are able to track it reliably over time within individuals. We were thrilled with the result and believe delta has great potential for use as a biomarker and outcome measure in future clinical trials, as well as pre-clinical studies because we saw the same result in our mouse-model data.”

Few authentic biomarkers for Angelman syndrome have been found. Biomarkers must be objective, reliable, and repeatable in different settings in order to accurately determine whether a potential therapeutic is effective. This latest discovery checks all of those boxes. This ASF-funded published research takes a significant step forward in having viable tools to measure the success of pre-clinical and clinical drug trials. 

24 Apr

An article from UConn Health. See the article in UConn Today

Stem Cells Help UConn Researchers Identify Defects Causing Angelman syndrome

Researchers at UConn Health are using stem cells derived from patients with Angelman syndrome to identify the underlying cellular defects that cause the rare neurogenetic disorder, an important step in the ongoing search for potential treatments for Angelman and a possible cure.

Up until now, scientists trying to understand why the brain cells of individuals with Angelman fail to develop properly have relied primarily on mouse models that mimic the disorder.

By using human stem cells that are genetically identical to the brain cells of Angelman syndrome patients, researchers now have a much clearer and more accurate picture of what is going wrong.

In a study appearing today in the journal Nature Communications, the researchers report that the brain cells of individuals with Angelman syndrome fail to properly mature, causing a cascade of other developmental deficits that result in Angelman syndrome.

“We looked at the electrical activity of these brain cells and their ability to form connections, which is critical to the working circuits in the brain,” says UConn Health neuroscientist Eric Levine, the study’s lead author.

“We found that the cells from Angelman patients had impairments,” says Levine. “They didn’t develop the same way as they do in people who don’t have the disorder. They failed to develop mature electrical activity and they didn’t form connections as readily.”

Angelman syndrome appears in one out of every 15,000 live births. People with Angelman have developmental delays, are prone to seizures, and can have trouble walking or balancing. They have limited speech, but generally present a happy demeanor, frequently laughing and smiling.

The disorder occurs when a single gene that individuals inherit from their mother’s 15th chromosome is deleted or inactive. The paternal copy of that gene, known as UBE3A, is normally silenced in brain cells.

The research study led by Levine was done in collaboration with another research team at UConn Health led by developmental geneticist Stormy Chamberlain. Chamberlain is investigating the underlying genetic mechanisms that cause Angelman and how they might be reversed. Levine’s research team meanwhile is looking at the physiology behind the disorder or what happens in the brain when the maternal UBE3A gene is missing or fails to work properly.

“What’s interesting about this particular study is that Eric captured some of the first electrophysiological differences between Angelman syndrome neurons and typically developing neurons and it appears those primary deficits are setting up all of the other problems that are happening downstream,” says Chamberlain.

The human brain relies on electrical signals to process information. These signals pass between the neurons in our brain via special connections called synapses. In the current study, Levine found that at about three to five weeks into their development, brain cells in unaffected individuals ramp up their electrical activity while cells from Angelman patients do not. That failure to mature disrupts the ability of the Angelman cells to form proper synaptic connections, which is critical for learning, memory, and cognitive development.

“Other researchers haven’t seen this deficit in mouse models but we think it might have something to do with where they were looking,” says Chamberlain, who is a co-author on the current study. “In the mouse studies, researchers have been looking at either adults, juvenile, or early postnatal neurons. Eric is looking at some of the earliest changes in neurons that likely occur during fetal development.”

Angelman patients are very active in the ongoing research into the disorder. The induced pluripotent stem cells used in Levine’s research were derived from skin and blood cells donated by people with Angelman. Those cells were then reprogrammed into stem cells that were grown in the lab into brain cells that match the patient’s genetic makeup. This process allowed Levine to closely monitor how the cells developed from their very earliest stages in vitro and to see how they differed from control cells taken from people without the disorder.

To confirm that the cellular defects in the Angelman cells were caused by the loss of the UBE3A gene, Levine edited out the UBE3A gene in cells from the control group to see what would happen. Indeed, the same cascading chain of events occurred.

“In the control subjects who did not have Angelman, we basically knocked out the gene in order to mimic the Angelman defect,” Levine says. “If you do that early enough in development, you see all of the things go wrong in those cells. Interestingly, if you wait and knock out the gene later in development, you only see a subset of those deficits.”

Those results led Levine to believe that the delayed development of electrical activity in the brain cells from patients with Angelman is one of the driving factors causing other defects to occur. That knowledge is important for the development of possible drugs to combat Angelman. If scientists can stop that initial electrical failure from happening, it might prevent the other developmental problems from happening as well. Researchers with Ionis Pharmaceuticals from Carlsbad, Calif. also participated in the current study.

With this new information in hand, Chamberlain and Levine are taking the research to the next level. They want to know exactly how the loss of the UBE3A gene causes the development of electrical activity in the early brain cells of Angelman patients to stop.

Another benefit of the current study is that the stem cell model created by Chamberlain and Levine can now be used to screen potential therapeutics for Angelman. Having the ability to monitor human brain cells in the lab will allow researchers to test dozens if not hundreds of compounds to see if they reverse Angelman’s cellular defects. The same process could be applied by scientists looking into other disorders.

And that’s good news.

“The Angelman Syndrome Foundation was proud to fund Dr. Levine’s research in 2011 and we are thrilled to see the results,” says Eileen Braun, executive director of the national nonprofit organization that funds Angelman syndrome research and supports individuals with Angelman and their families. “Having results published in Nature Communications, a prestigious, peer-reviewed journal, illustrates the validity of this research, which ultimately helps us understand more about Angelman syndrome and helps lead us to our ultimate goal of treatments and a cure.”

Individuals interested in supporting people with Angelman syndrome and Angelman research are welcome to participate in a walk supporting the Angelman Syndrome Foundation on May 20 at Northwest Park, 448 Tolland Turnpike, Manchester, CT. Registration opens at 8:30 a.m. The walk beings at 10 a.m. Donations are encouraged and accepted. The University of Connecticut is one of the sponsors of the walk.

11 May

2016 Walk Receives Local Coverage in Utah

The Deseret News in Utah published a story on ASF Walk Coordinator, Michelle Gilbert, and her son Aiden.

Aiden Gilbert is a happy 11-year-old from South Jordan. He likes to spend time with his family, and he is very social.

“He is a really fun kid,” said his mother, Michelle Gilbert. “It’s just a real joy to interact with him.”

When he was almost 2 years old, Aiden was diagnosed with Angelman syndrome . . .

See the full Deseret News article here.

20 Apr

Research has answered some questions about UBE3A’s role in seizures

ASF-funded research conducted at Dr. Ben Philpot’s lab at the University of North Carolina-Chapel Hill has answered some questions about UBE3A’s role in seizures in individuals with Angelman syndrome, and also illustrated additional work that needs to be done.

Published in the prestigious research journal, Neuron, the research sought to answer the question: how are seizures affected by where—not just when—UBE3A is expressed in the brain?

The research team, led by Matt Judson, PhD in Philpot’s lab, found that UBE3A loss specifically from GABAergic neurons can cause seizures in an Angelman syndrome mouse model. It was previously unclear which cell classes were relevant, and there were reasons to believe that UBE3A loss in both excitatory and inhibitory neurons was important. The research showed that loss of UBE3A from inhibitory neurons, but not excitatory neurons, is enough to cause seizures. This illustrates that both timing AND location of UBE3A restoration are important in reducing seizures in AS. This is relevant to gene therapy and other treatment approaches. More work needs to be done to determine different cell types and pathways to further understand the link between UBE3A and seizures in Angelman syndrome.

See an article about the research in Spectrum.

Access the full issue (requires paid subscription).

19 Apr

ASF Walk in Mexico City

The inaugural Walk location in Mexico City, Mexico has brought the opportunity to raise awareness on an international level.  An article recently appeared in Miraflores that provided information about Angelman Syndrome and offered the idea that Angelman Syndrome families are not alone in this battle – and this is our opportunity to help.

See the article about Angelman Syndrome in Miraflores.

05 Jan

Angelman Syndrome Family Retreat at Center for Courageous Kids

The holidays aren’t over yet! Our gift to you is a family weekend retreat at the Center for Courageous Kids, a camp designed exclusively for children with disabilities and their family members.


“CCK offers an amazing weekend for families to relax and be together … treating all kids, with or without special needs, as equals. We enjoyed the fellowship at meals, swimming, horseback riding, fishing, bowling … And we had a great volunteer to assist us with our kids. We look forward to going back this year!”

– Christi Gould, AS mother who previously attended the camp with her family.
 

 

Here are the details:

  • Thirty — yes, 30! — AS families will have the opportunity to come together for a full weekend of fun, fellowship, acceptance and respite.
  • The camp is designed for the entire AS family to attend together. Children with  AS must be at least five years old.
  • Families will enjoy a number of fun activities, including archery, bowling, canoeing, horseback riding, arts and crafts, and so much more!
  • The weekend retreat goes from Friday afternoon to Sunday afternoon; families must commit to the entire weekend.
  • The ASF is partnering with the Center for Courageous Kids to jointly fund this weekend getaway as a gift to you! Families only need to cover their travel costs to and from camp.

Want to see pictures of families enjoying the camp? Visit the Center for Courageous Kids’ Facebook page!

Don’t miss this incredible opportunity!

Families interested in attending should complete the Family Retreat online application as soon as possible before space fills up, as only 30 families will be able to attend. The Center for Courageous Kids will review all family applications and notify you of your acceptance into the family weekend, at which time more detailed information will be provided.

CAMP INFORMATION

Center for Courageous Kids
1501 Burnley Road
Scottsville, KY 42164

Office of Camper Recruitment
Contact: Alvin Farmer
Phone: (270) 618-2912
Email: alvin@courageouskids.org

 

IMPORTANT DATES

February 1, 2016 – Deadline to Apply for a Volunteer Position
February 15, 2016  – Deadline to Register
April 1-3, 2016 – ASF Family Weekend Retreat

 

VOLUNTEER OPPORTUNITIES

Calling all volunteers who want to attend and help our families! Twelve volunteer slots are available for those who want to help and support families during the weekend retreat in various roles. It’s a three-day commitment including attendance at the volunteer orientation at the start of the weekend. All food and lodging costs are covered; travel to the camp is the responsibility of the volunteer. Center for Courageous Kids provides a complete list of detailed volunteer job descriptions. Background checks will be required.

To apply for a volunteer position contact Kelli Firquin, Volunteer Recruiter at kelli@courageouskids.org and complete the online application.

 

30 Nov

The ASF Celebrates the Opening of the New Angelman Syndrome Clinic at Mayo Clinic

One-Stop Facility Provides Comprehensive Support for Individuals with Angelman syndrome from Infancy through Adulthood

ROCHESTER, Minn., November 30, 2015 – Mayo Clinic and the Angelman Syndrome Foundation (ASF) announced today the opening of Mayo Clinic’s Angelman Syndrome Clinic, one of only three Angelman syndrome-specific clinics in the country. The facility, established by Mayo Clinic with support from the ASF, focuses on serving the comprehensive medical needs of individuals with Angelman syndrome. With the creation of the clinic, individuals with Angelman syndrome and their families can access multiple subspecialists and a variety of medical resources in one setting, as opposed to visiting multiple locations across the nation. The Angelman Syndrome Clinic leverages the variety of expertise and specialized care available at Mayo Clinic to help individuals with Angelman syndrome from infancy through adulthood.

Occurring in one in 15,000 live births, Angelman syndrome is a neurogenetic disorder often misdiagnosed as autism or cerebral palsy that causes severe neurological impairment, appears in newborns and lasts for a lifetime. During fetal development, the loss of function of a particular gene in the brain occurs, resulting in neurons functioning improperly and causing deficits in development. Individuals with Angelman syndrome experience developmental delay, lack of speech, seizures, walking and balance disorders, and typically exhibit a happy demeanor characterized by frequent smiling, laughter and excitability.

Mayo Clinic’s mission is to inspire hope and contribute to health and well-being by providing the best care for each patient through integrated clinical practice, education and research.  “We provide each patient and family with a team of experts using integrated case management to conduct a complete evaluation of the patient’s condition, for which a treatment plan is then developed and tailored to each patient’s needs. We are thrilled to provide this very specialized care for individuals with Angelman syndrome and their families with the help of ASF,” said Ralitza Gavrilova, M.D., a Mayo Clinic neurologist and geneticist who will lead the effort.

With the goal of improving quality of life for individuals with Angelman syndrome, Mayo Clinic provides seamless access to a care team of pediatric and adult specialists in the following areas: clinical genomics, epilepsy, sleep medicine, psychiatry, speech pathology, clinical nutrition, orthopedics, neuropsychiatry, gastroenterology, physical medicine, rehabilitation and social work. Upon arrival at Mayo Clinic, patients first meet with Clinic Director Dr. Gavrilova, and one of the Clinic Co-Coordinators, Sarah Mets or Marine Murphree, who are both certified genetic counselors. A review of past medical history, a comprehensive family history is conducted and discussion of a care plan occurs, followed by several days of consultations and testing with specialists who are all experts in Angelman syndrome. At the completion of the visit, a summary meeting occurs with the genetic counselor, who offers recommendations for the patient’s local health care providers.

“Our foundation has focused its mission on providing tangible, accessible support for individuals with Angelman syndrome and their families, and this clinic is another representation of that and further delivers on our promise of helping open a total of 17 clinics across the country during the next few years,” said Eileen Braun, executive director of the ASF and mother to a young woman with Angelman syndrome. “To have the exceptional team and vast medical resources available at Mayo Clinic accessible to our families is tremendous, and we could not be more proud to support the Mayo Clinic to bring the Angelman Syndrome Clinic to life to help our families when they need it most.”

The Angelman Syndrome Clinic is located at Mayo Clinic’s main campus at 200 First St. SW, Rochester, Minn. 55905. Patients can contact Mayo Clinic after Dec. 1 to request an appointment through the central appointment office at (507) 538-3270, with coordinated visits to the Angelman Syndrome Clinic to begin in Feb. 2016. Referring physicians can call (800) 533-1564 or click here to refer a patient.

For more information about Mayo Clinic, please visit www.mayoclinic.org.

ABOUT MAYO CLINIC

Mayo Clinic is a nonprofit organization committed to medical research and education, and providing expert, whole-person care to everyone who needs healing. For more information, visit http://mayocl.in/1ohJTMS or http://newsnetwork.mayoclinic.org/.

 

06 Aug

Angelman Syndrome Foundation-Funded Research at University of North Carolina-Chapel Hill Leads to Breakthrough in AS- and Autism-related research

Research from the lab of Dr. Mark Zylka, a leading AS researcher and associate professor of cell biology and physiology at the University of North Carolina-Chapel Hill, has made a few exciting discoveries related to Angelman syndrome. The research, which has implications for AS and shed light on many genetic intricacies not previously known about autism, was published today in Cell, a top neuroscience publication—a tremendous accomplishment for the research team.

The team’s research has identified a pathway that regulates the activity of the UBE3A enzyme. If a specific phosphate is attached to the UBE3A enzyme, the enzyme is turned off. If that phosphate is removed, the UBE3A enzyme is turned on. The research published in Cell discusses the implications for Dup15q syndrome, where the UBE3A enzyme needs to be turned off; and for AS, where research needs to both produce more of the enzyme activity, by turning on the paternal copy of the UBE3A gene, as well as turn on the UBE3A enzyme.

“What the exciting work by Zylka and colleagues indicates is that UBE3A levels are (almost certainly) very tightly regulated during development, and treatments designed at restoring UBE3A expression must be undertaken with great care, due to the potential dangers of overexpression and excessive UBE3A activity,” said Lynne Bird, M.D., Professor of Clinical Pediatrics at the University of California-San Diego.

You can click here to read UNC’s press release, which further discusses the research’s implications for autism and Dup15q syndrome.

You can click here to access the full paper in Cell.

The Angelman Syndrome Foundation funded this research in its 2013 research grant cycle. The National Institutes of Health, the Foundation for Angelman Syndrome Therapeutics, and Autism Speaks also funded this research.