Announcing the 15q Clinical Research Network
18 Nov

Announcing the 15q Clinical Research Network

Angelman Syndrome Foundation and Dup15q Alliance Announce Development of the International Clinical Research Network in efforts to help those living with 15q syndromes. 

Thousands of families affected by Angelman syndrome (AS) and dup15q syndrome will soon have greater access to comprehensive clinical care through the development of The 15q Clinical Research Network. The Angelman Syndrome Foundation (ASF) and the Dup15q Alliance are proud to announce that through this collaborative effort the 15q Clinical Research Network would expand to 20 operating clinics to serve patients with Angelman syndrome or dup15q syndrome.

For more than a decade the ASF and Dup15q Alliance have been supporting multidisciplinary clinics to ensure up-to-date evidence-based clinical care for individuals with Angelman and Dup15q syndromes. What began as a few clinics has grown to almost 20 sites in the U.S. with four international sites between the two organizations. These clinics are working to standardize care for those with these disorders, a critical step forward as we approach clinical trials. Additionally, they serve as a platform for robust clinical research including collection of integral natural history data.

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Angelman and dup15q syndromes are two rare conditions that occur due to a problem with the same region of the 15th chromosome. Because of that, they share symptoms (developmental delays, GI problems, seizures) that often require specialized care. Due to the rareness of the syndromes, local general practitioners and even specialized doctors often do not have a thorough knowledge of the complications and treatments. To get the care they need some families have traveled far to receive care for their loved ones at the clinics that have dotted the U.S. map. 

Both foundations realized that there were far too many families who were not able to travel to receive specific care, so they embarked on a mission to dramatically expand the clinical reach of the networks and provide truly comprehensive care across the country by combining forces. 

ASF CEO, Amanda Moore, says, “We believe that partnering with the Dup15q Alliance will allow us to increase our reach to the AS community and provide the best care for our families. Comprehensive and specific care is critical for AS families throughout the stages of their journey — by partnering with Dup15q Alliance we are able to reach thousands of more families with care and support by bringing AS Clinics to their geographical location.”

The joint expansion of the clinical network will also expand the amount of clinical trial sites in the future, increase research and publications, and add important clinical data that can impact the therapeutic treatments around both disorders. 

Vanessa Vogel-Farley, Executive Director of Dup15q Alliance states, “One of the biggest challenges those who have 15q related disorders face is finding clinical support that is educated about their needs and that are effective activated partners in the complex medical care of their loved one. The collaboration between the Angelman and dup15q syndrome communities in the establishment of the 15q Clinical Research Network helps to alleviate that burden, by expanding the number of locations where expert providers are available, and  establish a system for transferring care of the patients back to their local providers through education and seamless communication with providers.”

This is the not the first time that ASF and Dup15q Alliance have worked together.  Because of the common issues with the 15th chromosome, the past several years ASF and Dup15q Alliance have co-hosted a research symposium every two years.  Many researchers that study Angelman syndrome also study dup15q syndrome and the research symposium brings them together to share ideas and collaborate, advancing research and clinical trials. 

Angelman syndrome is a rare genetic disorder caused by the loss of function of a specific gene (15q chromosome) during fetal development, resulting in severe neurological impairment present at birth and lasting for a lifetime. Symptoms vary and include severe developmental delays, speech impairments, seizures, walking and balance disorders, and frequent laughter and excitability. While there is no definitive count, it is estimated that Angelman syndrome occurs in one in every 15,000 live births.

Dup15q syndrome is a clinically identifiable syndrome that results from the duplication (or multiplication) of the same portion of the 15q chromosome that is deleted in Angelman Syndrome.  Also known as chromosome 15q11.2-q13.1 duplication syndrome, this is a neurodevelopmental disorder that confers a strong risk for autism spectrum disorder, epilepsy, and intellectual disability, etc. It is estimated to occur in one out of every 8,000-10,000 live births.

14 Aug

Published Paper: Microcephaly in AS Mice

Published Paper: Microcephaly in AS Mice

See the paper by Matthew Judson in The Journal of Neuroscience

Summary

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.

11 May

Biomarker for Clinical Trials in Angelman Syndrome

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. 

20 Apr

UBE3A’s Role in Seizures

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).