The Angelman Syndrome Foundation is issuing the following statement regarding healthcare legislation in the US because of its impacts on the lives of people with Angelman syndrome and their families.
Statement from Angelman Syndrome Foundation Board of Directors:
The healthcare proposals currently being debated in Congress include provisions that could have potentially devastating impacts on people with Angelman syndrome (AS) and their families. In support of people with AS and their caregivers, the Angelman Syndrome Foundation (ASF) strongly opposes any effort to cut or cap Medicaid, a program that provides vital services to children and adults with AS. Without sufficient Medicaid funding for home and community-based services, institutionalization would be the only viable option available to many of our loved ones with AS. Proposals to cut funding for school-based services funded by Medicaid and to eliminate affordable healthcare options for caregivers would have major impacts on our community as well. The Angelman community, including the ASF, is fighting for our loved ones with every tool we have. Please stand with us and contact your members of Congress to let them know why Medicaid and affordable healthcare are important to your family.
- Major national organizations including The Arc, The National Organization for Rare Disorders and the National Down Syndrome Society all oppose cuts and caps to Medicaid.
- “Medicaid is the main source of funding for over 77% of the supports and services that individuals with intellectual and/or developmental disabilities (I/DD) use to live in the community.” (Source: ARC)
- “In 2017, 68 percent of school superintendents reported using Medicaid funds for school nurses, counselors, speech therapists, and other health professionals.”
See the paper by Matthew Judson in The Journal of Neuroscience.
Many individuals with Angelman syndrome (AS) have microcephaly—a smaller head and brain size—than typically developing individuals. This microcephaly is not present at birth, but becomes evident sometime during the first 18 months of life, indicating a problem with brain growth. During this early phase of development, the brain typically grows very quickly and must develop in a precise manner to support normal brain functions. In AS, the brain grows more slowly, and this correlates with developmental delay, impaired motor function, and EEG abnormalities. The ASF-funded research team, led by Ben Philpot, Ph.D., studied microcephaly in AS mice and sought to determine the cause of reduced brain size in the mice. The results were published in the August 2nd issue of The Journal of Neuroscience.
The team examined the brain growth of AS mice during early development and found that they develop microcephaly after birth. Although newborn AS mice have the same sized brains as their neuro-typical counterparts, the brains of AS mice grow more slowly, and are thus smaller than their neuro-typical littermates by the time they are juveniles. As with individuals with AS, this microcephaly persists into adulthood. Notably, Philpot’s group showed that changes in the amount of white matter accounted for most of the microcephaly in AS mice. White matter contains bundles of axons, which are the long, slender portions of neurons that transmit electrical signals to other neurons or muscles. Axons are coated with a substance called myelin, which acts to insulate the electrical activity of axons. Philpot and colleagues found that although the amount of myelin was normal in adult AS mice, the axons in AS mice were smaller in diameter than the mice without AS. These smaller axons correlated with deficits in nerve conduction in the AS mice. Future research will help determine exactly how the axon diameter deficit in AS mice arises during development, whether it might be related to delays in myelination, and how it could contribute to behavioral phenotypes.
White matter deficits have been previously reported in individuals with AS. The ASF recently funded a collaborative group including Drs. Ben Philpot, Mark Shen, Heather Hazlett, and Ron Thibert to study this process in children and young adults with AS. Preliminary data from this work was presented at the Angelman Syndrome Foundation’s 2017 Research Symposium. More work in this important area of brain research is needed to determine if the white matter deficits observed in individuals with AS are caused by changes in axon diameter, as predicted by Philpot’s recent findings in AS mice. Importantly, if the extent of white matter structural deficits proves to correlate with the severity of impairments in nerve conduction and motor skills performance in individuals with AS, then measurement of white matter may serve as a helpful biomarker to gauge responsiveness to a potential treatment.
Angelman Biomarkers and Outcome Measures Alliance and Roche begin patient-centered qualitative research to inform potential outcome measures for Angelman syndrome clinical trials
Nashville, Tenn. (June 22, 2017) – A collaborative group of parent-driven organizations seeking a cure for Angelman syndrome has teamed up with F. Hoffmann-La Roche Ltd, (Roche), one of the world’s largest pharmaceutical and diagnostics companies, in the first phase of a study that will support the design of human clinical trials and treatment development for the disorder.
Roche has committed funding to create an Angelman syndrome conceptual model. Roche as a leader in personalized healthcare is taking a patient-centered approach to drug and treatment development.
According to Roche, the first phase of the study aims to better understand the impact of Angelman syndrome on patients and their families through interviews with caregivers and physicians around the world.
“The findings of this research will be a key step towards identifying and developing the best outcome measures and biomarkers for future clinical trials,” says Dr. Tom Willgoss, principal scientist, Roche.
The study signals a new movement into the human testing phase of possible drug and therapy development for Angelman syndrome.
“To have such a cutting-edge biotech giant join all of us in the quest for a treatment and cure for Angelman syndrome is a very hopeful sign of significant movement for our families who struggle with the impact of this disorder,” says Dr. Allyson Berent, DVM, DACVIM, chief science officer for FAST (Foundation for Angelman Syndrome Therapeutics).
Dr. Stormy Chamberlain, chair of the scientific advisory committee for the Angelman Syndrome Foundation (ASF), agreed that this next phase of development in Angelman research takes a critical step in matching the needs of patients with Angelman syndrome to possible treatment and measurement strategies.
“We are all working together to determine the needs of families with Angelman syndrome in terms of new treatments and medications,” says Chamberlain.
FAST and ASF joined efforts with Agilis Biopharmaceuticals to create the Angelman Biomarkers and Outcome Measures Alliance (A-BOM) in 2016. The alliance of foundations and biopharmaceutical firms works to help researchers identify the best ways to measure clinical progress in Angelman syndrome in an effort to design better trials to test the effectiveness of new experimental treatments. A-BOM is encouraging the families, caregivers and physicians of Angelman syndrome patients to participate in this effort by joining the Angelman registry. The registry assists researchers in collecting strategic information about the disorder from patients and their physicians. The registry can be found online at angelmanregistry.info.
“We need rigorous ways to measure how potential treatments may improve the quality of life for individuals with Angelman syndrome and their families,” says A-BOM’s director, Dr. Terry Jo Bichell. “Roche’s conceptual model will set a standard that will help researchers determine what to measure, how to measure it, and how to interpret their findings when they are trying to identify possible treatments.”
Initial findings for the first phase of the study are expected in 2017. The research team plans to interview the caregivers and clinicians of approximately 33 patients with Angelman syndrome in its sample.
About The Angelman Biomarkers and Outcome Measures Alliance (A-BOM)
The Angelman Biomarkers and Outcome Measures Alliance (A-BOM) is a new group formed by both FAST (Foundation for Angelman Syndrome Therapeutics) and the Angelman Syndrome Foundation, together with researchers and pharmaceutical corporations to help move new treatments to the clinical trial phase. A-BOM includes scientists, foundations and corporations that are all working together to share in research, studies, trials and stories to help people with Angelman syndrome.
ASF-funded research published in the Journal of Neurodevelopmental Disorders has identified that delta—a frequency of brain rhythms identifiable by EEG scans—can 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.
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.
Ovid Therapeutics, a privately held biopharmaceutical company based in New York City, announced that the U.S. Food and Drug Administration has granted orphan drug designation to OV101 for the treatment of patients with Angelman syndrome.
San Diego Chargers legend LaDainian Tomlinson kicked off his Celebrity Golf Tournament Thursday at the Sycuan Golf Resort, in El Cajon, CA. In partnership with Oggi’s Sports | Brewhouse | Pizza the tournament is spreading awareness for Angelman Syndrome.
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.
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.
Access the full issue (requires paid subscription).