Angelman Syndrome Clinic Opens in Chicago, IL
22 Aug

Rush University Medical Center Launches Angelman Syndrome Clinic

The First Comprehensive Clinic in Illinois Providing Support for Individuals with Angelman Syndrome

(CHICAGO) – Rush University Medical Center and the Angelman Syndrome Foundation (ASF), a national nonprofit organization headquartered in Aurora, Ill., announced the official opening of the Angelman Syndrome Clinic at Rush Children’s Hospital. The Angelman Syndrome Clinic at Rush is the first and only in Illinois and one of only eight in the U.S.

“Rush is focused on serving the comprehensive medical needs of individuals with Angelman syndrome,” said Dr. Cesar Ochoa-Lubinoff, co-director of the Angelman Clinic at Rush. “With the creation of the clinic, individuals with Angelman syndrome and their families can access multiple subspecialists and a variety of medical resources in one setting, as opposed to visiting multiple locations across the nation.”

“Individuals with Angelman syndrome have extreme challenges obtaining the care they need as they grow into adults,” said Dr. Elizabeth Berry-Kravis, co-director of the Angelman Clinic at Rush. “Our hospital is uniquely positioned to provide services to this portion of the population and their families.”

“Our partnership with the ASF has allowed us to further meet these needs and provide the comprehensive medical services that improve patient and families’ quality of life,” said Ochoa-Lubinoff.

Occurring in one in 15,000 live births, Angelman syndrome is a neurogenetic disorder often misdiagnosed as autism or cerebral palsy – that causes severe neurological impairment, appears in newborns and lasts for a lifetime. During fetal development, the loss of function of a particular gene in the brain occurs, resulting in neurons functioning improperly and causing deficits in development.

Individuals with Angelman syndrome experience developmental delay, lack of speech, seizures, walking and balance disorders, and typically exhibit a happy demeanor characterized by frequent smiling, laughter and excitability. Caregivers need to provide constant supervision and often experience pain, stress, anxiety and exhaustion.

The Angelman Syndrome Clinic at Rush is unique as it can leverage the variety of expertise and specialized care available at the Medical Center to help individuals with Angelman syndrome from infancy through adulthood.

The purpose of the clinic is to reduce the frequency and severity of Angelman syndrome symptoms that interfere with function, such as seizures, behavior and sleep problems. In addition, the clinic will work with families to develop educational recommendations to optimize educational programming for individuals with Angelman syndrome, thus helping these individuals achieve their full developmental potential.

With the ultimate goal of improving quality of life for individuals with Angelman syndrome, the clinic provides comprehensive access to neurologists, epileptologists, developmental-behavioral pediatricians, psychologists, and a sleep medicine physician, rehabilitation medicine specialist, gastroenterologist, pulmonologist, speech language pathologist, physical/occupational therapist, genetic counselor, social worker and nutritionist all specializing in Angelman syndrome.

As part of the commitment to improving the lives of patients and families living with Angelman syndrome, the medical team participates in the latest clinical research protocols and trials.

“Opening this clinic at Rush University Medical Center – in our own headquarter’s backyard – is an exciting milestone for ASF. Our mission is to provide help and support to individuals with Angelman syndrome and their families across the country, and this new clinic will bring the best, comprehensive medical care to so many in need,” said Eileen Braun, executive director of the Angelman Syndrome Foundation and mother to a young woman with Angelman syndrome. “We are thrilled to help bring this significant resource to the greater Chicago area, and we could not be more proud to partner with Rush University Medical Center and their remarkable team of professionals to bring this clinic to life.”

The Angelman Syndrome Clinic at Rush University Medical Center is located at 1725 W. Harrison St., Suite 710. Chicago. Appointments can be made by calling (312) 942-9645.

For more information about Angelman syndrome and the ASF, please visit www.angelman.org. For more information about Rush Children’s Hospital at Rush University Medical Center, please visit www.rush.edu.

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ABOUT THE ANGELMAN SYNDROME FOUNDATION
The Angelman Syndrome Foundation’s mission is to advance the awareness and treatment of Angelman syndrome through education and information, research, and support for individuals with Angelman syndrome, their families and other concerned parties. The ASF sponsors Angelman syndrome research through grants to researchers pursuing treatments and a cure for Angelman syndrome. Since 1996, the ASF has funded 101 research grants totaling more than $9.5 million. The ASF has awarded a majority of these funds ($9.2 million) beginning in 2005. For more information about the ASF, visit www.angelman.org.

About Rush
Rush is an academic health system whose mission is to improve the health of the patients and the diverse communities it serves with nationally recognized health care, education, research and a commitment to community partnerships. The Rush system comprises Rush University Medical Center, Rush University, Rush-Copley Medical Center and Rush Oak Park Hospital, as well as numerous outpatient care facilities. Rush University, with more than 2,500 students, is a health sciences university that comprises Rush Medical College, the College of Nursing, the College of Health Sciences and the Graduate College.

Highlights from the 2018 Angelman Syndrome Foundation/Dup15q Research Symposium
17 Aug

Attendees Share Highlights from the 2018 Angelman Syndrome Foundation/Dup15q Research Symposium

The most brilliant minds in Angelman and Dup15q syndromes collaborated for two days in Chapel Hill, North Carolina last week, sharing unpublished data and knowledge that is pushing the AS community closer toward treatments and a cure for AS.

As the leading AS research meeting in the world, the ASF/Dup15q Research Symposium left each attendee—ranging from seasoned scientists and AS clinicians to post-docs and graduate students, who are all passionate about AS—inspired and super-charged to further their work in AS.

 

Several attendees from different backgrounds have shared their key insights from the ASF/Dup15q Research Symposium:

Dr. Steven Siegelbaum
Dr. Steven Siegelbaum
Chair, Department of Neuroscience, Columbia University Medical Center
Grandfather to a 3-year-old boy diagnosed with Angelman syndrome

“As both a neuroscientist…and as a grandfather with a 3 year old grandson with AS, I found the meeting to be extremely informative. It appears that the field is at the cusp of developing both useful small molecule therapeutic approaches to treat some of the symptoms of AS (and Dup15q) and gene therapeutics to correct the underlying loss of Ube3a in AS. Because AS is clearly associated with pleiotropic effects on underlying neural function (e.g. alterations in neural structure, tonic inhibition, axon diameter, ion channel expression) and pleiotropic behavioral changes (cognitive function, sleep, motor development, language), I think it will be important in the future to gain a clearer understanding of the relation between the two. I believe the expanded use of MRI in individuals with AS and Dup15q will be important to correlate alterations in brain structure (including white matter loss) with behavior and with treatments, and to relate findings in humans to results in mouse models.”

 

 

Stormy Chamberlin
Dr. Stormy Chamberlain
ASF Scientific Advisory Committee Chair
Associate Professor, Dept. of Genetics and Genome Sciences, UConn Health

“Here are my top three key takeaways from the Symposium:

  1. We have a lot of work going on in clinical space including trying to identify measurable features to be used as outcome measures/biomarkers for upcoming clinical trials. This truly shows how far and quickly the science and understanding of AS is advancing. Attendees even made comments about how many clinicians from many specialities presented, which is great!
  2. I was impressed by the presentations about new, novel ways to modulate RNA that might be helpful for Angelman syndrome—they used approaches that haven’t been thought of before for AS. It was a perfect example of people thinking outside of the box, and how we can apply other learnings to AS to solve issues with Ube3a.
  3. Overall, there was a tremendous amount of resource and information sharing. People are truly coming to this meeting to learn, network and collaborate, and they are sharing work that is yet unpublished—but highly advanced and important to finding treatments and a cure for AS. This includes the sharing of information from the Angelman Syndrome Clinics, which is impressive data. The collaboration was evident in a nearly all presentations, and it is truly amazing. I am so grateful for where we are, and for where we are going!”

 

 

Rossella Avagliano Trezza


Rossella Avagliano Trezza
Post-doc in ASF-funded researcher Dr. Ype Elgerma’s lab

“The ASF/Dup15q Research Symposium was a very stimulating experience, it’s amazing to see how the clinical and scientific worlds come together to deepen the knowledge on these disorders and broaden our horizons. As Ben Philpot mentioned in his closing remarks, much progress has been made in the past three to five years and this conference highlighted some of the most interesting findings. Even though I truly believe any contribution to the meeting is instrumental to move our research forward, I think a few key talks made the real difference:  

  • Targeting and eliminating RNA in RNA disorders: RNA editing is transient which in terms of a specific targeting is a great advantage. 
  • Measurable parameters to determine altered morphology in human-induced pluripotent stem cell (iPSC)-derived neurons: As science progresses further, it’s more and more evident the need for biological systems that mimic the human brain. While we are far away from generating a faithful representation of a human brain in vitro, iPSC-derived neurons offer a very close approximation. The work of Judy Bloom and Stormy Chamberlain is in this sense an essential outcome measure.
  • The comparison between Christianson and Angelman syndromes: I have always found fascinating the possibility of finding new Ube3a interactors via Angelman-like disorders, and current research that is focusing on common aspects in the pathophysiology and cellular biology of both Angelman and Christianson syndromes is incredibly interersting.

Overall I think these type of symposia where the top scientists of the field have the possibility of talking and sharing ideas are the true fuel of scientific research. There is no progress without confrontation and the ASF/Dup15q conference allowed just that.

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

— 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

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

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

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

Healthcare Legislation in the US
18 Sep

Statement Regarding Healthcare Legislation in the US

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/

2017 Research Symposium Recap
21 Aug

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.

14 Aug

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.

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.

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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.

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