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

Highlights from the 2018 Angelman Syndrome Foundation/Dup15q Research Symposium

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minds in Angelman and Dup15q syndromes collaborated for two days in Chapel Hill, North Carolina last week, sharing unpublished data and knowledge that is pushing the AS community closer toward treatments and a cure for AS.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

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

Healthcare Legislation in the US
18 Sep

Healthcare Legislation in the US

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/

14 Aug

Published Paper: Microcephaly in AS Mice

Published Paper: Microcephaly in AS Mice

See the paper by Matthew Judson in The Journal of Neuroscience

Summary

Many individuals with Angelman syndrome (AS) have microcephaly—a smaller head and brain size—than typically developing individuals. This microcephaly is not present at birth, but becomes evident sometime during the first 18 months of life, indicating a problem with brain growth. During this early phase of development, the brain typically grows very quickly and must develop in a precise manner to support normal brain functions. In AS, the brain grows more slowly, and this correlates with developmental delay, impaired motor function, and EEG abnormalities. The ASF-funded research team, led by Ben Philpot, Ph.D., studied microcephaly in AS mice and sought to determine the cause of reduced brain size in the mice. The results were published in the August 2nd issue of The Journal of Neuroscience.

The team examined the brain growth of AS mice during early development and found that they develop microcephaly after birth. Although newborn AS mice have the same sized brains as their neuro-typical counterparts, the brains of AS mice grow more slowly, and are thus smaller than their neuro-typical littermates by the time they are juveniles. As with individuals with AS, this microcephaly persists into adulthood. Notably, Philpot’s group showed that changes in the amount of white matter accounted for most of the microcephaly in AS mice. White matter contains bundles of axons, which are the long, slender portions of neurons that transmit electrical signals to other neurons or muscles. Axons are coated with a substance called myelin, which acts to insulate the electrical activity of axons. Philpot and colleagues found that although the amount of myelin was normal in adult AS mice, the axons in AS mice were smaller in diameter than the mice without AS. These smaller axons correlated with deficits in nerve conduction in the AS mice. Future research will help determine exactly how the axon diameter deficit in AS mice arises during development, whether it might be related to delays in myelination, and how it could contribute to behavioral phenotypes.     

White matter deficits have been previously reported in individuals with AS. The ASF recently funded a collaborative group including Drs. Ben Philpot, Mark Shen, Heather Hazlett, and Ron Thibert to study this process in children and young adults with AS. Preliminary data from this work was presented at the Angelman Syndrome Foundation’s 2017 Research Symposium. More work in this important area of brain research is needed to determine if the white matter deficits observed in individuals with AS are caused by changes in axon diameter, as predicted by Philpot’s recent findings in AS mice. Importantly, if the extent of white matter structural deficits proves to correlate with the severity of impairments in nerve conduction and motor skills performance in individuals with AS, then measurement of white matter may serve as a helpful biomarker to gauge responsiveness to a potential treatment.

22 Jun

Development of Potential Outcome Measures for AS Clinical Trials

Angelman Biomarkers and Outcome Measures Alliance and Roche begin patient-centered qualitative research to inform potential outcome measures for Angelman syndrome clinical trials

Nashville, Tenn. (June 22, 2017) – A collaborative group of parent-driven organizations seeking a cure for Angelman syndrome has teamed up with F. Hoffmann-La Roche Ltd, (Roche), one of the world’s largest pharmaceutical and diagnostics companies, in the first phase of a study that will support the design of human clinical trials and treatment development for the disorder.

Roche has committed funding to create an Angelman syndrome conceptual model. Roche as a leader in personalized healthcare is taking a patient-centered approach to drug and treatment development.

According to Roche, the first phase of the study aims to better understand the impact of Angelman syndrome on patients and their families through interviews with caregivers and physicians around the world.

“The findings of this research will be a key step towards identifying and developing the best outcome measures and biomarkers for future clinical trials,” says Dr. Tom Willgoss, principal scientist, Roche.

 The study signals a new movement into the human testing phase of possible drug and therapy development for Angelman syndrome.

“To have such a cutting-edge biotech giant join all of us in the quest for a treatment and cure for Angelman syndrome is a very hopeful sign of significant movement for our families who struggle with the impact of this disorder,” says Dr. Allyson Berent, DVM, DACVIM, chief science officer for FAST (Foundation for Angelman Syndrome Therapeutics).

Dr. Stormy Chamberlain, chair of the scientific advisory committee for the Angelman Syndrome Foundation (ASF), agreed that this next phase of development in Angelman research takes a critical step in matching the needs of patients with Angelman syndrome to possible treatment and measurement strategies.

“We are all working together to determine the needs of families with Angelman syndrome in terms of new treatments and medications,” says Chamberlain.  

FAST and ASF joined efforts with Agilis Biopharmaceuticals to create the Angelman Biomarkers and Outcome Measures Alliance (A-BOM) in 2016. The alliance of foundations and biopharmaceutical firms works to help researchers identify the best ways to measure clinical progress in Angelman syndrome in an effort to design better trials to test the effectiveness of new experimental treatments. A-BOM is encouraging the families, caregivers and physicians of Angelman syndrome patients to participate in this effort by joining the Angelman registry. The registry assists researchers in collecting strategic information about the disorder from patients and their physicians. The registry can be found online at angelmanregistry.info.

“We need rigorous ways to measure how potential treatments may improve the quality of life for individuals with Angelman syndrome and their families,” says A-BOM’s director, Dr. Terry Jo Bichell. “Roche’s conceptual model will set a standard that will help researchers determine what to measure, how to measure it, and how to interpret their findings when they are trying to identify possible treatments.”

Initial findings for the first phase of the study are expected in 2017. The research team plans to interview the caregivers and clinicians of approximately 33 patients with Angelman syndrome in its sample.

###
About The Angelman Biomarkers and Outcome Measures Alliance (A-BOM)

The Angelman Biomarkers and Outcome Measures Alliance (A-BOM) is a new group formed by both FAST (Foundation for Angelman Syndrome Therapeutics) and the Angelman Syndrome Foundation, together with researchers and pharmaceutical corporations to help move new treatments to the clinical trial phase. A-BOM includes scientists, foundations and corporations that are all working together to share in research, studies, trials and stories to help people with Angelman syndrome.

11 May

Biomarker for Clinical Trials in Angelman Syndrome

ASF-funded Research Identifies Biomarker for Clinical Trials

ASF-funded research published in the Journal of Neurodevelopmental Disorders has identified that delta—a frequency of brain rhythms identifiable by EEG scanscan serve as a reliable biomarker for pre-clinical and clinical trials in Angelman syndrome. The research team, led by Dr. Mike Sidorov at the University of North Carolina-Chapel Hill, compared existing EEG data from the Angelman Syndrome Natural History Study to neuro-typical EEG data from Massachusetts General Hospital. The study showed that delta abnormalities can be seen across the brain of children with Angelman syndrome, and during both sleep and wake. 

“We focused on delta because it is the most commonly reported abnormality in AS EEG scans,” said Sidorov. “In doing so, we consistently found that nearly every individual with AS has increased delta compared to neuro-typical individuals.” Most importantly, we found that delta abnormalities can be quantified, said Sidorov. “By reducing delta to a single number, we are able to track it reliably over time within individuals. We were thrilled with the result and believe delta has great potential for use as a biomarker and outcome measure in future clinical trials, as well as pre-clinical studies because we saw the same result in our mouse-model data.”

Few authentic biomarkers for Angelman syndrome have been found. Biomarkers must be objective, reliable, and repeatable in different settings in order to accurately determine whether a potential therapeutic is effective. This latest discovery checks all of those boxes. This ASF-funded published research takes a significant step forward in having viable tools to measure the success of pre-clinical and clinical drug trials. 

24 Apr

Stem Cell Research at UConn Health

An article from UConn Health. See the article in UConn Today

Stem Cells Help UConn Researchers Identify Defects Causing Angelman syndrome

Researchers at UConn Health are using stem cells derived from patients with Angelman syndrome to identify the underlying cellular defects that cause the rare neurogenetic disorder, an important step in the ongoing search for potential treatments for Angelman and a possible cure.

Up until now, scientists trying to understand why the brain cells of individuals with Angelman fail to develop properly have relied primarily on mouse models that mimic the disorder.

By using human stem cells that are genetically identical to the brain cells of Angelman syndrome patients, researchers now have a much clearer and more accurate picture of what is going wrong.

In a study appearing today in the journal Nature Communications, the researchers report that the brain cells of individuals with Angelman syndrome fail to properly mature, causing a cascade of other developmental deficits that result in Angelman syndrome.

“We looked at the electrical activity of these brain cells and their ability to form connections, which is critical to the working circuits in the brain,” says UConn Health neuroscientist Eric Levine, the study’s lead author.

“We found that the cells from Angelman patients had impairments,” says Levine. “They didn’t develop the same way as they do in people who don’t have the disorder. They failed to develop mature electrical activity and they didn’t form connections as readily.”

Angelman syndrome appears in one out of every 15,000 live births. People with Angelman have developmental delays, are prone to seizures, and can have trouble walking or balancing. They have limited speech, but generally present a happy demeanor, frequently laughing and smiling.

The disorder occurs when a single gene that individuals inherit from their mother’s 15th chromosome is deleted or inactive. The paternal copy of that gene, known as UBE3A, is normally silenced in brain cells.

The research study led by Levine was done in collaboration with another research team at UConn Health led by developmental geneticist Stormy Chamberlain. Chamberlain is investigating the underlying genetic mechanisms that cause Angelman and how they might be reversed. Levine’s research team meanwhile is looking at the physiology behind the disorder or what happens in the brain when the maternal UBE3A gene is missing or fails to work properly.

“What’s interesting about this particular study is that Eric captured some of the first electrophysiological differences between Angelman syndrome neurons and typically developing neurons and it appears those primary deficits are setting up all of the other problems that are happening downstream,” says Chamberlain.

The human brain relies on electrical signals to process information. These signals pass between the neurons in our brain via special connections called synapses. In the current study, Levine found that at about three to five weeks into their development, brain cells in unaffected individuals ramp up their electrical activity while cells from Angelman patients do not. That failure to mature disrupts the ability of the Angelman cells to form proper synaptic connections, which is critical for learning, memory, and cognitive development.

“Other researchers haven’t seen this deficit in mouse models but we think it might have something to do with where they were looking,” says Chamberlain, who is a co-author on the current study. “In the mouse studies, researchers have been looking at either adults, juvenile, or early postnatal neurons. Eric is looking at some of the earliest changes in neurons that likely occur during fetal development.”

Angelman patients are very active in the ongoing research into the disorder. The induced pluripotent stem cells used in Levine’s research were derived from skin and blood cells donated by people with Angelman. Those cells were then reprogrammed into stem cells that were grown in the lab into brain cells that match the patient’s genetic makeup. This process allowed Levine to closely monitor how the cells developed from their very earliest stages in vitro and to see how they differed from control cells taken from people without the disorder.

To confirm that the cellular defects in the Angelman cells were caused by the loss of the UBE3A gene, Levine edited out the UBE3A gene in cells from the control group to see what would happen. Indeed, the same cascading chain of events occurred.

“In the control subjects who did not have Angelman, we basically knocked out the gene in order to mimic the Angelman defect,” Levine says. “If you do that early enough in development, you see all of the things go wrong in those cells. Interestingly, if you wait and knock out the gene later in development, you only see a subset of those deficits.”

Those results led Levine to believe that the delayed development of electrical activity in the brain cells from patients with Angelman is one of the driving factors causing other defects to occur. That knowledge is important for the development of possible drugs to combat Angelman. If scientists can stop that initial electrical failure from happening, it might prevent the other developmental problems from happening as well. Researchers with Ionis Pharmaceuticals from Carlsbad, Calif. also participated in the current study.

With this new information in hand, Chamberlain and Levine are taking the research to the next level. They want to know exactly how the loss of the UBE3A gene causes the development of electrical activity in the early brain cells of Angelman patients to stop.

Another benefit of the current study is that the stem cell model created by Chamberlain and Levine can now be used to screen potential therapeutics for Angelman. Having the ability to monitor human brain cells in the lab will allow researchers to test dozens if not hundreds of compounds to see if they reverse Angelman’s cellular defects. The same process could be applied by scientists looking into other disorders.

And that’s good news.

“The Angelman Syndrome Foundation was proud to fund Dr. Levine’s research in 2011 and we are thrilled to see the results,” says Eileen Braun, executive director of the national nonprofit organization that funds Angelman syndrome research and supports individuals with Angelman and their families. “Having results published in Nature Communications, a prestigious, peer-reviewed journal, illustrates the validity of this research, which ultimately helps us understand more about Angelman syndrome and helps lead us to our ultimate goal of treatments and a cure.”

Individuals interested in supporting people with Angelman syndrome and Angelman research are welcome to participate in a walk supporting the Angelman Syndrome Foundation on May 20 at Northwest Park, 448 Tolland Turnpike, Manchester, CT. Registration opens at 8:30 a.m. The walk beings at 10 a.m. Donations are encouraged and accepted. The University of Connecticut is one of the sponsors of the walk.

11 May

2016 Walk in Utah

2016 Walk Receives Local Coverage in Utah

The Deseret News in Utah published a story on ASF Walk Coordinator, Michelle Gilbert, and her son Aiden.

Aiden Gilbert is a happy 11-year-old from South Jordan. He likes to spend time with his family, and he is very social.

“He is a really fun kid,” said his mother, Michelle Gilbert. “It’s just a real joy to interact with him.”

When he was almost 2 years old, Aiden was diagnosed with Angelman syndrome . . .

See the full Deseret News article here.