Designation of Unique ICD-10 Code for Angelman Syndrome
19 Jun

Availability of Dedicated Code Will Advance Research and Development of Treatments for this Unique, Well-defined Syndrome and Lead to Improved Clinical Care

Nashville, TN, June 19, 2018 — The Angelman Biomarkers and Outcome Measures (A-BOM) Alliance today announced that the National Center for Health Statistics has designated a specific ICD-10 code for Angelman syndrome, a neurodevelopmental disorder caused by genetic mutations. The designation of the ICD-10 code resulted from a combined effort of the A-BOM Alliance, leaders in the biopharmaceutical industry, family physicians, specialists, pharmacists and other health professionals. The new ICD-10 code (Q93.51) will take effect on October 1, 2018.

Until now, Angelman syndrome was included in the ICD-10 code Q93.5, which contains a large group of disorders with different genetic causes and different treatment strategies and is not specific to Angelman syndrome. The dedicated ICD-10 code for Angelman syndrome will make it easier for the field to conduct epidemiologic research and retrospective studies, determine true prevalence and morbidity and mortality rates, recruit patients for clinical trials, track outcomes of clinical interventions, and develop protocols for standard of care.

“We are grateful to everyone who joined with A-BOM to make the new ICD-10 code a reality, including the clinicians who contributed their expertise, and the companies and foundations that provided funding and letters of support,” said Terry Jo V. Bichell, MPH, Ph.D., director and scientific officer of the A-BOM Alliance. “The designation of a unique ICD-10 code for Angelman syndrome is a significant development that will lead to improved clinical care for patients with this disorder. What a difference one number will make!” 

The ICD-10 is the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD), a medical classification list from the World Health Organization (WHO). ICD-10 codes are used to document an individual’s medical condition for epidemiology, research, health insurance billing and reimbursement, and administration. The United States uses the ICD-10-CM, a Clinical Modification of the WHO standard, while Europe and other parts of the world use the ICD-10.

“Ovid would like to congratulate everyone involved in the successful effort to designate a unique ICD-10 code for Angelman syndrome,” said Jeremy Levin, DPhil, MB, BChir, chairman and chief executive officer of Ovid Therapeutics. “This is an important development for the field and we were pleased to lend our support. With clinical trials of investigational therapeutics under way, a dedicated ICD-10 code will help healthcare professionals better understand the impact of the illness, track outcomes of clinical interventions, and fully identify the patient population that could benefit.”

 

About Angelman Syndrome
Angelman syndrome is a genetic disorder that is characterized by delayed development, intellectual disability, severe speech impairment, problems with movement and balance, seizures, sleep disorders and anxiety. The most common cause of Angelman syndrome is the disruption of a gene that codes for ubiquitin protein ligase E3A (UBE3A). Angelman syndrome affects approximately 1 in 15,000 people in the U.S. There are currently no U.S. Food and Drug Administration (FDA)-approved
therapies for the treatment of Angelman syndrome. Angelman syndrome is associated with a reduction in tonic inhibition, a function of the delta (δ)-selective GABAA receptor that allows a human brain to decipher excitatory and inhibitory neurological signals correctly without being overloaded. If tonic inhibition is reduced, the brain becomes inundated with signals and loses the ability to separate background noise from critical information.

About the A-BOM Alliance
The Angelman Biomarkers and Outcome Measures (A-BOM) alliance was formed by the Foundation for Angelman Syndrome Therapeutics and the Angelman Syndrome Foundation, together with researchers, clinicians and pharmaceutical corporations to help move new treatments to the clinical trial phase. There are many medications and treatments for Angelman syndrome that are coming close to being ready for clinical trials. The field as a whole needs rigorous ways to measure whether these treatments can improve the quality of life for patients and families. Our alliance members work
together to share data, research, trial design and stories to help people with Angelman syndrome. For more information, visit https://www.angelmanbiomarkers.org/

Dr. Mark Zylka recognized as a 2017 AAAS Fellow
22 Nov

Congratulations to Dr. Mark Zylka who has been recognized as a 2017 American Association for the Advancement of Science (AAAS) Fellow! The AAAS fellows date back to 1874 and have included such prestigious recipients as Thomas Edison and Margaret Mead. More recently, five of this year’s Nobel laureates were also AAAS Fellows.

The ASF is proud to fund the work Dr. Zylka has done to improve the lives of individuals with Angelman syndrome!

Read more on the American Association for the Advancement of Science website.

Dr. Art Beaudet to receive McKusick Leadership Award
16 Oct

Congratulations to Dr. Arthur Beaudet on being named the 2017 recipient of the Victor A. McKusick Leadership Award from the American Society of Human Genetics. 

Dr. Beaudet has been a pioneering force in Angelman syndrome research; it’s truly because of him that AS research has progressed to where it is today! Whether it be identifying the Ube3a gene as the cause of AS or working on several treatments for AS—including his recent ASF-funded study in 2014 on ASOs. 

Find out more about the award and Dr. Beaudet’s accomplishments

Statement regarding healthcare legislation in the US
18 Sep

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.

Facts:

  • Major national organizations including The Arc[1], The National Organization for Rare Disorders[2] and the National Down Syndrome Society[3] 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)[4]
  • “In 2017, 68 percent of school superintendents reported using Medicaid funds for school nurses, counselors, speech therapists, and other health professionals.”[5]

 


[1] http://www.huffingtonpost.com/entry/why-you-should-care-about-looming-medicaid-cuts_us_58a33332e4b0cd37efcfed80

[2]https://rarediseases.org/wp-content/uploads/2014/11/NORDs-Principles-for-Health-Coverage-Reform-Final.pdf

[3] https://www.ndss.org/About-NDSS/Newsroom/Recent-News/ndss-statement-on-bcra/

[4] https://blog.thearc.org/2017/05/11/passage-ahca-real-life-consequences-people-disabilities/

[5] https://blog.thearc.org/2017/05/11/passage-ahca-real-life-consequences-people-disabilities/

Research Symposium Recap
21 Aug

Every summer, the world’s top researchers in AS come together at the ASF Research Symposium to discuss the latest in AS cutting-edge research.

Below, is a synopsis of the scientific presentations from the 2017 ASF Research Symposium developed by Dr. Stormy Chamberlain, ASF’s Scientific Advisory Committee chair.

 

Overview of AS research landscape 
Ben Philpot, Ph.D., University of North Carolina 
Becky Burdine, Ph.D., Princeton University

Drs. Philpot and Burdine summarized research efforts to frame the symposium. They briefly discussed efforts to identify UBE3A substrates, two of the major therapeutic approaches—gene therapy and unsilencing of the paternal copy of UBE3A, phenotype-specific treatments (i.e., seizure, anxiety, sleep approaches), and biomarkers.  Biomarkers are features that can be objectively measured to determine whether a treatment is working. Finally, unanswered research questions and challenges facing the development of therapeutics were discussed.

 

UBE3A isoform localization and function 
Ype Elgersma, Ph.D., Erasmus University Medical Center, Rotterdam, Netherlands

A keynote talk by Dr. Elgersma reported on his ongoing work using a clever ASF-funded mouse model to determine whether UBE3A is required throughout life, or whether it is only necessary for a defined window during development. He also reported preliminary results regarding the locations in the cell of the three UBE3A isoforms and how much of the total UBE3A protein each isoform comprises. This work on the isoforms was also a project funded by ASF.

 

Deciphering the role of CAMK2A in Angelman syndrome mice 
Geeske van Woerden, Ph.D., Erasmus University Medical Center, Rotterdam, Netherlands

Dr. van Woerden discussed her ongoing work to understand the relationship between CamKII phosphorylation and Angelman syndrome. Specifically, she is determining whether CamKII dysfunction in humans can cause AS-like phenotypes. In the second part of her talk, she discussed her ASF-funded efforts to explore cognitive tests in AS the mouse model.

 

Arc-dependent homeostatic synaptic plasticity is altered in Angelman syndrome model mice 
Jason Shepherd, Ph.D., University of Utah

Dr. Shepherd discussed work showing that ARC and UBE3A do not physically interact as some reports had suggested. However, he found that ARC protein is still misregulated in AS mouse neurons. Dr. Shepherd reported data exploring how ARC becomes misregulated and how this misregulation leads to defects in homeostatic synaptic plasticity, the process by which neurons regulate their own excitability relative to the activity around them. This ASF-funded work was recently published in Frontiers in Molecular Neuroscience.

 

Gene therapy for central nervous system diseases 
Steven Gray, Ph.D., University of North Carolina

An exciting talk by Dr. Gray introduced us to the current research landscape of AAV-mediated gene therapy for disorders of the CNS. He presented important data showing how AAV gets distributed throughout the brain during a therapeutic infusion: how many cells and how far it spreads throughout the brain depending on how it is delivered. He discussed some of the honest drawbacks of AAV-mediated gene therapy, but also discussed his recent successful treatment of giant axonal neuropathy using this type of gene therapy, which was a first-in-human trial of gene therapy for a brain disorder. Stay tuned for an exciting announcement from ASF regarding gene therapy.

 

Disrupted synaptic transmission and protein homeostasis in an Angelman syndrome mouse model 
Shengfeng Qiu, Ph.D., University of Arizona College of Medicine

Dr. Qiu presented his work delving deeply into the function of specific neurons in the AS mouse brain, especially the prefrontal cortex. His preliminary data suggest altered neuronal connectivity (i.e. synapses) that is dependent on developmental stage and/or age. In addition, his data suggest that autophagy, a process by which cells dispose of proteins, may be impaired in AS mouse neurons. He hypothesizes that enhancing neuronal autophagy may correct some issues in the AS brain.

 

MRI and DTI in children with Angelman syndrome reveals white matter pathology linked to motor deficits 
Mark Shen, Ph.D., University of North Carolina

Dr. Shen gave a riveting talk reporting deficits in the white matter of children with AS.  This ASF-funded study, involving children 3-10 years old, was carried out at the ASF-funded Angelman Syndrome Clinic at UNC-Chapel Hill. Decreased white matter volume and compromised white matter integrity were seen. These findings were specific to AS, and not seen in kids with autism or Fragile X syndrome. Mark also showed some of the recently published data from the Philpot lab reporting similar findings in AS mice. AS mice have decreased brain volume and white matter. The parallel white matter changes seen in both humans and mice may be an important biomarker to inform how well therapies may be working. Although structural changes in white matter seems like a bad thing, it is so important to have this specific biomarker in order to see whether therapies might be working.

 

BDNF-enhancer drug facilitates learning in Angelman mice 
John Marshall, Ph.D., Brown University

Dr. Marshall discussed his ongoing work with CN2097, a compound that restores the disrupted BDNF signaling in AS mice. The mechanism of how this works was investigated. This work has implications for learning and memory in AS, and may suggest a novel therapeutic approach. 

 

Clinical trials for targeted treatments in neurodevelopmental disorders:  Past experience and new directions 
Elizabeth Berry-Kravis, M.D., Ph.D., Rush University Medical Center

A keynote talk by Dr. Berry-Kravis ended the Tuesday talks. Dr. Berry-Kravis has been involved in various clinical trials to test therapeutics for Fragile-X syndrome. She discussed the design, outcomes, and lessons learned from each of these approaches, as well as shared her experience interacting with the FDA. She made important points about placebo effects, establishing outcome measures to assess improvements in key domains expected to be impacted by the therapy, clinical trial design–including models for evaluating a therapeutic effect on learning, potential need to stratify patients based on age or severity to see significant efficacy of a therapeutic, and need to find ways to test young children with developmental disorders before determining if a targeted therapeutic has benefit.

 

Eye gaze and pupillary response in Angelman syndrome 
Logan Wink, M.D., Ph.D., Cincinnati Children’s Hospital Medical Center

Dr. Wink spoke about her preliminary data using eye gaze and pupillary response as a read-out in individuals with AS. These measures are objective ways to measure an individual’s response to stimulus, however, some features of AS may make these measurements difficult. Dr. Wink reported that 47% of individuals with AS (8 of 17) completed the eye tracking task, which sought to determine whether individuals with AS preferred a social scene versus a geometric scene. This task has been previously used to determine social preference in autism spectrum disorders.

 

Understanding healthcare utilization among patients with Angelman syndrome:  Results from the AS natural history study 
Raquel Cabo, Ovid Pharmaceuticals 
Lynne Bird, M.D., University of California, San Diego

Ms. Cabo and Dr. Bird presented data mined from the natural history study to determine the Health Resources Usage (HRU) and Medical Services Usage (MSU) by individuals with AS. Data collected from 302 individuals with AS revealed the frequency of hospitalization, surgery and medication, as well as the usage of early childhood intervention and specific therapies (PT, OT, ST) amongst individuals with AS. Patients with deletions had significantly more seizure-related hospitalizations, and used more prescription medications. Sleep, seizures and gastrointestinal problems were the main reasons for prescription and over-the-counter medication use.

 

Developmental Milestones in children with Angelman syndrome—findings from the AS natural history study 
Anjali Sadhwani, Ph.D., Boston Children’s Hospital

Dr. Sadhwani presented similar data from the Natural History Study regarding developmental milestones to determine the ages at which participants achieved motor and language skills. The attainment of specific skills was determined across different genetic etiologies (deletion, UBE3A mutation, UPD, or ICD).

 

Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome 
Mike Sidorov, Ph.D., University of North Carolina

An interesting talk by Dr. Sidorov discussed collaborative efforts from the Philpot group, Dr. Ron Thibert, and Dr. Lynne Bird reporting the quantification of EEG signatures for use as a biomarker for AS. Specifically, the group quantified delta power and dynamics in individuals with AS as well as the mouse model. They found that delta power is significantly increased in both humans and mice lacking UBE3A. Furthermore, they developed a computational tool, called PARADE, which automates the quantification of EEG signatures in both species. This ASF-funded work, which suggests a useful and robust biomarker for anticipated clinical trials, was recently published in Journal of Neurodevelopmental Disorders.

 

Anxiety in individuals with Angelman syndrome  
Anne Wheeler, Ph.D., University of North Carolina

Dr. Wheeler described her work in the ASF-funded AS clinic at UNC where she is studying anxiety in individuals with AS. Anxiety seems to be a significant issue for many individuals with AS, as evidenced by Anne’s study as well as robust attendance at talks addressing anxiety during the ASF Family Conference.

 

AAV-mediated strategies for the treatment of Angelman syndrome
Jodi Cook, Ph.D, Agilis Biotherapeutics
Edwin Weeber, Ph.D, University of South Florida

Dr. Cook updated the group on their progress to develop an AAV-based gene therapy for AS. Agilis licensed an AAV therapeutic for AADC-Deficiency from an academic lab in Taiwan that has data on 23 treated subjects. Jodi presented their positive results, supporting the gene therapy approach. Dr. Weeber from the University of South Florida continued and described the preclinical studies being performed using AAV to deliver UBE3A as a gene replacement in the AS mouse model. Positive results for rescue of the synaptic plasticity and memory defects were described using a human UBE3A gene. In addition, a brief description was provided for a novel gene deletion rat model for AS undergoing initial characterization.

 

Mapping UBE3A effects on sociability to a subcellular compartment, autism protein interaction network, and circuit. 
Matthew Anderson, M.D., Ph.D., Harvard Medical School

A talk by Dr. Anderson summarized data from his recent publication describing sociability in AS mice and mice with two extra copies of Ube3a. In brief, he found that AS mice have increased social interactions and Ube3a overexpressing mice had decreased social interactions. His studies suggest that this may be mediated through the Cbln1 gene in mice. This work has been published in Nature.

 

EEG as a biomarker to assess the efficacy of therapeutics in Angelman syndrome 
Anne Anderson, M.D., Ph.D., Baylor College of Medicine

Dr. Anderson analyzed EEG data from individuals with AS who were enrolled in the minocycline clinical trial. She described the difficulty in reading the EEG data from the study due to differences in the program that stores EEG data. However, upon successfully reading and quantifying these EEGs, she was able to see reduction of delta power, which is an improvement in AS individuals 8 weeks after they stopped minocycline. It is not clear whether this reflects an improvement due to minocycline or a response to removal of the drug. Minocycline is currently not recommended for use to treat AS.

 

Rescue of hippocampus-dependent behaviors and physiology in a mouse model of Angelman syndrome by deletion of the Ephexin5 gene.
Ms. Gabrielle Sell, B.S., Johns Hopkins University

An interesting talk by Ms. Sell, a graduate student in Dr. Seth Margolis’ lab discussed their recent work with Ephexin 5 (E5). Dr. Margolis’ lab had previously shown that E5 is a target for UBE3A. It is increased in AS and may contribute to changes in dendritic spines in the hippocampus. Gabrielle mated E5 knockout mice with AS mice to see if reduction of E5 could rescue some features of AS mice. She found that E5 reduction did not rescue all phenotypes in AS mice, but that certain hippocampal-specific behavioral, cell biological, and electrophysiological phenotypes were, in fact, rescued. This data makes Ephexin5 an interesting potential therapeutic target for learning and memory phenotypes.

 

Establishing a molecular phenotype for Angelman syndrome induced pluripotent stem cell-derived neurons
Ms. Carissa Sirois, M.S., University of Connecticut School of Medicine

Ms. Sirois, a graduate student in Stormy Chamberlain’s lab discussed how she used CRISPR to correct an AS-causing mutation in UBE3A in human stem cells. She turned these cells—identical twins with and without AS—into neurons and asked whether the AS cells had physiological changes. She also compared gene expression genome-wide between AS and typical neurons and identified differences. She is using these approaches to determine if ASOs can restore AS phenotypes in human neurons and to determine how different UBE3A isoforms function.

14 Aug

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.

22 Jun

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.

11 May

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.

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