Category Archives: Research

Positive Topline Data from Phase 2 STARS Trial of OV101 for the Treatment of Angelman Syndrome
06 Aug

Positive Topline Data from Phase 2 STARS Trial of OV101 for the Treatment of Angelman Syndrome

Positive Topline Data from Phase 2 STARS Trial of OV101 for the Treatment of Angelman Syndrome

— OV101 achieved primary endpoint of safety and tolerability —
— Robust and statistically significant improvement (p=0.0006) in the first prespecified efficacy endpoint(CGI-I) observed at 12 weeks of treatment in once-daily dose group compared to placebo —
— STARS data support plans to advance OV101 development and discuss with regulators next steps for a registrational pathway —
— Conference call and webcast today at 8:00 a.m. EDT —

NEW YORK – August 6, 2018 – Ovid Therapeutics Inc. (NASDAQ: OVID), a biopharmaceutical company committed to developing medicines that transform the lives of people with rare neurological diseases, today announced that the Phase 2 STARS trial of OV101 achieved its primary endpoint of safety and tolerability. The investigational medicine showed a favorable safety profile and was well tolerated in adults and adolescents with Angelman syndrome. OV101 is the only selective extrasynaptic GABAA receptor agonist in development shown to mediate tonic inhibition, a key underlying pathophysiological mechanism of Angelman syndrome. Ovid’s founder, president and chief scientific officer, Matthew During, M.D., DSc,FACP, will present the data today at the 2018 Angelman Syndrome Foundation/Duplication15q Research Symposium in Chapel Hill, North Carolina.

The Phase 2 STARS international study is the first industry-sponsored, randomized, doubleblind,placebo-controlled clinical trial for Angelman syndrome. The study randomized 88 patients across three groups: a once-daily or twice-daily dose of OV101 or placebo. At the prespecified efficacy analysis at 12 weeks of treatment, OV101 showed a statistically significant improvement compared to placebo in the physician-rated clinical global impressions of improvement (CGI-I) – a measure commonly used in clinical trials that allows the physician to capture a constellation of clinical symptoms. CGI-I was ranked first in the topline statistical plan. Subsequent analyses in the hierarchy were conducted on a prespecified subset of scales across the domains of behavior, sleep and gait. While the analysis of these prespecified subsets did not show a statistically significant difference from placebo, full data analyses on these domains are ongoing and will be communicated in the future. Ovid intends to discuss these data with regulatory authorities to determine the next steps for a registrational pathway. Based on these data, the company plans to initiate in the fourth quarter of 2018 an open-label extension study (named ELARA); Angelman syndrome patients who completed any prior OV101 study may be eligible to receive the investigational medicine in this study.

Angelman syndrome is a rare, lifelong, genetic disorder that affects 1 in 15,000 people in the U.S. It is characterized by severe impairment in behavior, learning, verbal communication, motor skills, and sleep, and there are no FDA-approved medicines or an established treatment paradigm for this condition. If approved, OV101 could be the first medicine to specifically target a key underlying neurological dysfunction of Angelman syndrome — impaired tonic inhibition that is most commonly caused by a disruption of the UBE3A gene.

“We are excited by these data, as this is the first demonstration of positive clinical effect on overall symptomology in Angelman syndrome,” said Jeremy Levin, DPhil, MB, BChir, chairman and chief executive officer of Ovid Therapeutics. “In collaboration with the Angelman community, we designed a robust study to evaluate prespecified endpoints that may pave the way for a registrational pathway for a disorder that has no previously approved medicines. These data are a tribute to the patients and their families and we thank them.”

“These initial data from the STARS study are encouraging, particularly the statistically significant improvement in overall symptoms that we see in the CGI-I scale in the once-daily dosing group. Angelman syndrome is a complex disorder and the CGI-I scale captures the totality of global neurological deficits and helps to define the impact of medicines on the individual and their families,” said Ron Thibert, D.O., MsPH, chairperson, STARS clinical trial steering committee, director, Angelman syndrome clinic at Mass General Hospital for Children, and assistant professor at Harvard Medical School. “The data reported today are the first data in Angelman syndrome to show a compound specifically targeting the syndrome having a clinical effect. Ovid is the first company to have conducted a double-blind, placebo-controlled study in Angelman syndrome, providing important clinical and scientific data. Based on these data, I believe OV101 has the potential to offer a clinically meaningful benefit specific to people living with Angelman syndrome.”

“The STARS study was designed to provide information to allow us to progress the development of OV101,” said Amit Rakhit, M.D., MBA, chief medical and portfolio management officer of Ovid Therapeutics. “With these findings, we have advanced our understanding of relevant endpoints to evaluate key symptoms of Angelman syndrome. Furthermore, we demonstrated that a once-daily dose of OV101 could be sufficient to drive clinically meaningful benefit to patients. We look forward to discussing the data with regulatory authorities to inform our future development plans.”

STARS Phase 2 Topline Data Summary and Design
STARS was a 12-week, double-blind, placebo-controlled Phase 2 study. Eighty-eight patients (adults, n=66; adolescents, n=22) aged 13 to 49 years of age diagnosed with Angelman syndrome were randomized at 13 clinical trial sites in the U.S. and Israel. The study randomized patients to one of three arms: once-daily (QD) dose of OV101 at night (15mg), twice-daily (BD) dose of OV101 (10mg in the morning and 15mg at night), and placebo.

The intent to treat (ITT) population was 88 patients. A modified intent to treat (mITT) analysis of 87 patients (mean age = 22.6), which includes any patient who enrolled in the study and received at least one dose of study drug, was performed to evaluate the efficacy endpoints.

The primary endpoint of the trial was to assess the safety and tolerability of OV101 compared to placebo. The STARS trial explored the clinical utility of OV101 on improvements in clinical global impressions, maladaptive behavior, sleep, and gross and fine motor skills.

Primary Endpoint: Safety and Tolerability Data
The study met its primary endpoint of safety and tolerability given that the adverse events (AEs) with OV101 treatment were similar to placebo treatment, with the majority of AEs being mild. OV101 showed a favorable risk profile and was well tolerated through 12 weeks of treatment. Overall, the data are consistent with the favorable risk profile observed in previous insomnia trials with this investigational medicine.

The most common AEs reported in the trial were vomiting, somnolence, irritability, aggression, and pyrexia.

Table 1: Most Frequent Adverse Events*

Table 1: Most Frequent Adverse Events

Events occurring in greater than 5 percent (two or more patients) compared to placebo in either treatment arm included pyrexia, rash, seizure, enuresis and myoclonic epilepsy.

Adverse Events Occurring More Frequently in OV101 Arms vs. Placebo

Serious adverse events (SAEs) of seizure were reported in two patients: one patient in the QD dose experienced a seizure and that was deemed unrelated to study drug; one patient experienced a seizure in the BID dose group and that was assessed as possibly related to study drug by the investigator.

Treatment discontinuations due to adverse events were low. One patient in the placebo arm discontinued compared to no patients and three patients in the once-daily dose group and twicedaily dose group, respectively.

  • Placebo arm: one patient with irritability
  • Twice-daily arm: one patient with myoclonus; one patient with seizure, and one patient with irritability/anxiety/sleep disorder

Efficacy Endpoint Data
At 12 weeks of treatment, the first prespecified efficacy endpoint (CGI-I) demonstrated a robust and statistically significant difference (p=0.0206; Fisher’s Exact test) between the combined OV101 treatment arms and placebo. This reflects an improvement in two-thirds of the combined treatment groups versus one-third in placebo.

Table 3: Response Based on CGI-I at Week 12; Comparison to Placebo

In the prespecified analysis using the rigorous Mixed Model Repeated Measures (MMRM), which evaluated each OV101 treatment arm independently against placebo, the difference in CGI-I mean score at 12 weeks was statistically significant (p=0.0006) in the once-daily OV101 group versus placebo and also in the combined OV101 treatment group versus placebo (p=0.0103).

Table 4: Mean CGI-I Symptoms Overall Score – by Dose Group at Week 12; Comparison to Placebo

In a post-hoc analysis of patients who were “much” or “minimally” improved having a CGI-I score of ≤3, the data suggest that younger patients who received a once-daily dose had the greatest response to OV101 compared to older age groups.

Table 5: Patients Who were ‘Much’ or ‘Minimally’ Improved in CGI-I Score (≤3) (Post-hoc Analysis)

Ovid Therapeutics plans to present the full clinical data from the STARS study at an upcoming medical meeting.

ELARA 1-year Extension Study
In the fourth quarter of 2018, Ovid expects to initiate ELARA, an open-label extension study that will enable individuals with Angelman syndrome who completed any prior OV101 study to be eligible to receive the investigational medicine. The study will use once-daily dosing and will assess long term safety and tolerability in addition to efficacy measures.

Ovid Therapeutics has created a website specifically to provide disease education on Angelman syndrome. Learn more at anglemansyndrome.com.

Conference Call and Webcast Information
Ovid Therapeutics will host a live conference call and webcast today, August 6, 2018, at 8:00 a.m. Eastern Time. The live webcast can be accessed by visiting the Investors section of the company’s website at investors.ovidrx.com. Please connect at least 15 minutes prior to the live webcast to ensure adequate time for any software download that may be needed to access the webcast. Alternatively, please call 866-830-1640 (U.S.) or 210-874-7820 (International) to listen to the live conference call. The conference ID number for the live call is 8994338. A replay of the webcast will be available on the company’s website for two weeks following the live conference call.

About Angelman Syndrome
Angelman syndrome is a genetic disorder that is characterized by a variety of signs and symptoms. Characteristic features of this disorder include 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 loss of function of the gene that codes for ubiquitin protein ligase E3A (UBE3A), which plays a critical role in nerve cell communication, resulting in impaired tonic inhibition. Individuals with Angelman syndrome are highly social with a typical lifespan; however, they require constant support from a network of specialists and caregivers. 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 OV101
OV101 (gaboxadol) is believed to be the only delta (δ)-selective GABAA receptor agonist in development and the first investigational drug to specifically target the disruption of tonic inhibition, a central physiological process of the brain that is thought to be the underlying cause of certain neurodevelopmental disorders. OV101 has been demonstrated in laboratory studies and animal models to selectively activate the δ-subunit of GABAA receptors, which are found in the extrasynaptic space (outside of the synapse), and thereby impact neuronal activity through tonic inhibition.

Ovid is developing OV101 for the treatment of Angelman syndrome and Fragile X syndrome to potentially restore tonic inhibition and relieve several of the symptoms of these disorders. In preclinical studies, it was observed that OV101 improved symptoms of Angelman syndrome and Fragile X syndrome. This compound has also previously been tested in over 4,000 patients (over 1,000 patient-years of exposure) and was observed to have favorable safety and bioavailability profiles.

The FDA has granted Orphan Drug and Fast Track designations for OV101 for both the
treatment of Angelman syndrome and Fragile X syndrome. The U.S. Patent and Trademark Office has granted Ovid patents directed to methods of treating Angelman syndrome and Fragile X syndrome using OV101. The issued patents expire in 2035.

About Ovid Therapeutics
Ovid Therapeutics (NASDAQ: OVID) is a New York-based biopharmaceutical company using its BoldMedicine™ approach to develop therapies that transform the lives of patients with rare neurological disorders. Ovid has a broad pipeline of first-in-class medicines. The company’s lead investigational medicine, OV101, is currently in development for the treatment of Angelman syndrome and Fragile X syndrome. Ovid is also developing OV935/TAK-935 in collaboration with Takeda Pharmaceutical Company Limited for the treatment of rare developmental and epileptic encephalopathies (DEE).

For more information on Ovid, please visit http://www.ovidrx.com/.

Forward-Looking Statements
This press release includes certain disclosures that contain “forward-looking statements,” including, without limitation, statements regarding (i) timing and scope of any future clinical trials for OV101, (ii) the potential clinical benefit of OV101 to treat patients with Angelman syndrome, and (iii) the timing and results of any discussions with regulatory authorities regarding the registrational path for OV101. You can identify forward-looking statements because they contain words such as “will,” “believes” and “expects.” Forward-looking statements are based on Ovid’s current expectations and assumptions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that may differ materially from those contemplated by the forward-looking statements, which are neither statements of historical fact nor guarantees or assurances of future performance. Important factors that could cause actual results to differ materially from those in the forward-looking statements are set forth in Ovid’s filings with the Securities and Exchange Commission. Ovid assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available.

Contacts
Investors:
Lora Pike
Ovid Therapeutics Inc.
Senior Director, Investor Relations & Public Relations
lpike@ovidrx.com

Steve Klass
Burns McClellan, Inc
sklass@burnsmc.com
(212) 213-0006

Media:
Kelly Boothe, Ph.D.
W2O pure
kboothe@w2ogroup.com
(415) 946-1076

Elliot Fox
Group Director, Media Relations
W2O Group
efox@w2ogroup.com
(212) 257-6724

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

Designation of Unique ICD-10 Code for Angelman Syndrome

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

Dr. Mark Zylka recognized as a 2017 AAAS Fellow

Dr. Mark Zylka recognized as a 2017 AAAS Fellow

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

Dr. Art Beaudet to receive McKusick Leadership Award

Dr. Art Beaudet to receive McKusick Leadership Award

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

2017 Research Symposium Recap
21 Aug

2017 Research Symposium Recap

Highlights from the 2017 ASF Research Symposium

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.

22 Oct

Angelman Syndrome Clinics across the U.S.

ASF invests $1.5 million to support 17 Angelman Syndrome Clinics across the U.S.

Furthering its direct support of individuals with Angelman syndrome and their families, the Angelman Syndrome Foundation has committed $1.5 million to establish 17 comprehensive Angelman Syndrome Clinics across the country during the next few years. The ASF has strategically identified locations that are within a 4-hour driving distance for more than 85% of the AS population in the U.S.—meaning a majority of families (>85%) in the U.S. will not have to travel more than four hours to access their nearest clinic, which is a primary goal of the ASF’s in making the clinics as accessible as possible. Each clinic will receive a three-year funding commitment of $50,000 the first year, $30,000 the second year, and $10,000 the third year, to establish the clinics and support them until they are self-sustaining.

Currently, there are two Angelman Syndrome Clinics established in Chapel Hill, NC and Boston, MA. The ASF is in the final stages to open the next clinic in Rochester, MN and has requested proposals to establish the next clinics in San Diego and Houston, with Chicago to follow. In alphabetical order, future target cities include Atlanta, Cleveland, Dallas, Denver, Jacksonville, New York, Philadelphia, Salt Lake City, San Francisco, Seattle and St. Louis.

The purpose of the ASF’s Angelman Syndrome Clinics is to:

  • Provide a “one-stop-shop” medical and psychosocial resource from birth through adulthood for individuals with AS
  • Provide a foundation to support future clinical trials by having established sites with AS experts and patients in place to conduct those trials when they become available
  • Provide access to a variety of individuals all specializing in AS:  clinical geneticist, neurologist, psychiatrist, psychologist, speech language pathologist, physical/occupational therapist, genetic counselor, social worker, and nutritionist

Learn more about the Angelman Syndrome Clinics and current locations.

28 Feb

$104,500 in Grants for Angelman Syndrome Research

Angelman Syndrome Foundation Awards More Than $104,500 in Grants to Help Further Research

The Angelman Syndrome Foundation is continuing its commitment to research by awarding two grants focused on the therapeutic treatment of symptoms typically found in individuals with Angelman Syndrome (AS).  The more than $104,500 in grants were awarded to Dr. Sarika Peters of the Baylor College of Medicine in Houston, Texas, and Dr. Keith Allen of the MunroeMeyer Institute at the University of Nebraska in Omaha, Neb.

Dr. Peters will use her grant funding to research the use of conventional or complementary and alternative medicine (CAM) treatments for problem behaviors in Angelman Syndrome. By conducting an anonymous Web-based survey, Dr. Peters hopes to reach a large number of participants quickly and efficiently. The goal of her research is to have her findings help both parents and providers sort through safe, affordable and effective treatment options in the absence of strong empirical support for conventional or CAM treatments of AS problem behaviors. Dr. Allen will conduct his grant-funded research by evaluating the use of an evidence-based behavior management regimen that describes how to address sleep problems in children with AS.

“The Angelman Syndrome Foundation is dedicated to funding quality research efforts focused on the causes and therapeutic treatments of Angelman Syndrome,” said Executive Director Eileen Braun of the Angelman Syndrome Foundation. “After comprehensive review by the Angelman Syndrome Foundation Scientific Advisory Committee (SAC) the Board of Directors unanimously approved grants for Dr. Allen, Dr. Peters and their research objectives.” Since its first $10,000 research award in 1996 the Angelman Syndrome Foundation has funded more than $2.5 million in research projects, with a majority of these funds ($2.2 million) being awarded within the last three years.

28 Feb

More Than $1 Million Invested in Angelman Syndrome Research

Angelman Syndrome Foundation Funds More Than $1 Million in Research Grants for 2009

The Angelman Syndrome Foundation further solidified its dedication to research by increasing its grant award total to more than $1 million for 2009. Most recently, more than $988,000 in grants was awarded to six principle investigators, focusing on Angelman Syndrome (AS) research.

Dr. Benjamin Philpot of the University of North Carolina in Chapel Hill, N.C.; Dr. John Marshall of Brown University in Providence, R.I.; Dr. Eric Klann of New York University in New York; Dr. Peter Howley of Harvard Medical School in Boston, Mass.; Dr. Yong-Hui Jiang of Duke University in Durham, N.C.; and Dr. Scott Dindot of Texas A&M University in College Station, Texas, were the most recent recipients. Each recipient’s proposal was reviewed by the Angelman Syndrome Foundation’s Scientific Advisory Committee and approved by the Angelman Syndrome Foundation’s Board of Directors.

The approved proposals aim to target a variety of research approaches including:

  • Identifying pharmacological interventions that up regulate the paternal expression of UBE3A through a large scale drug screen, which could yield the prototype of therapy for AS (Philpot)
  • Targeting the underlying cause of the cognitive symptoms of AS, to ensure treatments are effective (Marshall)
  • Determining critical information concerning the therapeutic potential of approved pharmaceuticals, such as clozapine, for treating those with AS (Klann)
  • Identifying the substrates and pathways for the neuronal pathogenesis underlying AS and how they function, to assist in the treatment of AS symptoms (Howley)
  • Understanding the function of isoforms to help define genotype-phenotype correlation in humans with AS (Jiang)
  • Identifying the E6-AP isoform regulating synaptic maturation in neurons (Dindot)

“Being able to offer more than $1 million in research grants this year further supports the Angelman Syndrome Foundation’s commitment to improving the lives of those with AS,” said Executive Director Eileen Braun of the Angelman Syndrome Foundation. “Even amid these tough economic times, our aggressive funding of research continues to build a path toa cure, and with continued generous support we will be able to award even more funding next year.”

Two grants already announced earlier this year, totaling more than $104,500, bring the organization’s total grant awards for 2009 to more than $1 million. The two earlier grants announced in August focus on the therapeutic treatment of behavioral and sleep issues typically found in individuals with Angelman Syndrome (AS).  These grants were awarded to Dr. Sarika Peters of the Baylor College of Medicine in Houston, Texas, and Dr. Keith Allen of the Munroe-Meyer Institute at the University of Nebraska in Omaha, Neb.

The Angelman Syndrome Foundation is the largest research funder specifically dedicated to this neurogenetic disorder. The Foundation recently announced the Angelman Treatment and Research Institute (ATRI), which will direct the organization’s research funding and foster collaboration with more than 30 organizations, researchers and scientists worldwide.