The Weisenfeld Family talks with CNN about their child with AS
The Weisenfeld family spoke with CNN about their journey with Johanna, their 10-year-old daughter diagnosed with AS. A truly inspiring story to which almost all families can relate!
The Weisenfeld family spoke with CNN about their journey with Johanna, their 10-year-old daughter diagnosed with AS. A truly inspiring story to which almost all families can relate!
Promising ASF-funded research continues to move closer toward possible clinical trials, as announced today in a paper in Nature by Dr. Art Beaudet and his research team at Baylor College of Medicine.
The ASF funded this research in its 2011 and 2013 research grant cycles, as part of its $8 million and growing investment in AS research with the ultimate goal of finding a cure for AS.
More research will be conducted but pre-clinical trials in AS mice have proven that the paternal copy of Ube3a can be activated and that AS symptoms can be recovered, though more testing is needed to determine exactly how the cognitive deficits associated with AS are recovered.
Dan Harvey, chairman of the ASF’s Scientific Advisory Committee, has interpreted the research for AS families and developed the following summary about the research.
Neurotypical individuals have two versions of the Angelman syndrome gene (UBE3A), one from their mother (the maternal copy) and one from their father (the paternal copy) but only the one from the mother is expressed or “active.” In Angelman syndrome, the maternal copy is missing (deleted) or altered in some way to render it inactive. In 2008, Goal #1 of the ASF Research Roadmap was to aggressively explore activation of the silenced or “inactive” paternal copy of the AS gene (UBE3A) as a potential treatment for Angelman syndrome. The studies described in this article for Nature are the culmination of those efforts.
Recent studies by Philpot and colleagues demonstrated that Topotecan, a natural product derivative with various uses, unsilences the paternal copy of the AS gene in a non-specific manner. In this new article for Nature by Dr. Beaudet, Dr. Meng and their colleagues, it is demonstrated that a small DNA analog, known as an antisense oligonucleotide or ASO, can interact with the paternal copy of the AS gene and unsilence it in a highly specific manner.
Initial studies done with isolated neurons demonstrated that treatment with an ASO causes a long-lasting unsilencing of the paternal copy of the Ube3a gene.
Subsequent studies were done with AS mice. The ASO was directly injected into the brain of an AS mouse via a technique known as ICV (intracerebroventricular) injection. The ASO was well tolerated and partially unsilenced the paternal copy of the Ube3a gene. Additionally, it was highly specific for the AS gene, with no impact on other genes. Its activity was long lasting with unsilencing still observed sixteen weeks after treatment. When injected directly into a specific region of the brain know as the hippocampus, the part of the brain that manages cognition and learning, complete unsilencing of the paternal Ube3a was observed in the vicinity of the injection site.
Four weeks after treatment, AS mice treated with an ASO were subjected to behavioral testing and several of the behaviors typically observed in AS mice were reversed. In particular, memory impairment observed with AS mice was reversed after treatment. More extensive reversal of AS characteristics may require treatment at a younger age, a longer recovery time after treatment to allow greater rewiring of neural circuits, or a higher dosage of ASO.
In conclusion, the paper states: “Well tolerated delivery, broad tissue distribution, and long duration of action sets a framework for ASOs as a viable therapeutic strategy for diseases of the CNS (central nervous system), and builds enthusiasm toward further optimization and development of an ASO treatment for AS.”
The ASF continues to lead the charge in funding research that is making progress towards treatments and ultimately a cure for Angelman syndrome, having invested more than $8 million during the past decade in promising AS research.
A paper published today in the Proceedings of the National Academy of Sciences by Dr. Ben Philpot, Dr. Mark Zylka and Dr. Angela Mabb at the University of North Carolina at Chapel Hill uncovered additional findings about the Angelman syndrome gene, UBE3A.
Neurotypical individuals have two copies of the Angelman syndrome gene (UBE3A), one copy inherited from their mother (the maternal copy) and one from their father (the paternal copy). Only the maternal copy of UBE3A is “active” in neurons, thus mutation or deletion of this copy is sufficient to cause Angelman syndrome. The primary goal of the 2008 ASF Research Roadmap was to aggressively explore activation of the silenced or “inactive” paternal copy of UBE3A as a potential treatment for Angelman syndrome.
Recent studies by Dr. Ben Philpot, Dr. Mark Zylka, and Dr. Angela Mabb and their colleagues at the University of North Carolina at Chapel Hill demonstrated that Topotecan, a natural product derivative typically used to treat cancer, can unsilence the paternal copy of UBE3A. Topotecan thus represents a potential treatment for Angelman syndrome. However, it is essential to understand the potential side effects and the impacts of using Topotecan on brain function before moving into clinical trials. Accordingly, the studies described in this article from the Proceedings of the National Academy of Sciences continue the research group’s previous research in an effort to determine the consequences of using Topotecan or similar inhibitors in the brain.
The team took a step back from the mouse model and used an in vitro model, or neurons in a petri dish, because this provides a system to reliably and consistently deliver Topotecan to neurons.
This article illustrated that when neurons were treated with Topotecan, the goal of unsilencing the paternal copy of UBE3A was accomplished. However, during treatment, the neurons experienced a complete shutdown of activity—UBE3A was activated, but the specific cells that were treated stopped communicating with each other. However, normal neuronal activity was quickly restored once Topotecan was removed. This result is exciting because it suggests that most treatment side effects are likely to be fully reversible.
A goal of the research is to find a treatment strategy that can provide long-term UBE3A unsilencing, as was observed with their previous research, such that the side effects of Topotecan can be completely recovered in the short-term, as was observed in the current study.
The next step to this research is to identify novel and more efficient delivery methods using Topotecan or other inhibitors like Topotecan in an AS animal model to unsilence UBE3A, to evaluate potential side effects of these treatments, and to see if Angelman syndrome symptoms in the mouse model can be reversed following drug treatment.
Click here to access the PNAS paper.
Furthering its direct support of individuals with Angelman syndrome and their families, the Angelman Syndrome Foundation has committed $1.5 million to establish 17 comprehensive Angelman Syndrome Clinics across the country during the next few years. The ASF has strategically identified locations that are within a 4-hour driving distance for more than 85% of the AS population in the U.S.—meaning a majority of families (>85%) in the U.S. will not have to travel more than four hours to access their nearest clinic, which is a primary goal of the ASF’s in making the clinics as accessible as possible. Each clinic will receive a three-year funding commitment of $50,000 the first year, $30,000 the second year, and $10,000 the third year, to establish the clinics and support them until they are self-sustaining.
Currently, there are two Angelman Syndrome Clinics established in Chapel Hill, NC and Boston, MA. The ASF is in the final stages to open the next clinic in Rochester, MN and has requested proposals to establish the next clinics in San Diego and Houston, with Chicago to follow. In alphabetical order, future target cities include Atlanta, Cleveland, Dallas, Denver, Jacksonville, New York, Philadelphia, Salt Lake City, San Francisco, Seattle and St. Louis.
The purpose of the ASF’s Angelman Syndrome Clinics is to:
Every year, the Olsen Family—Keith, Denise and their children—hosts a Tractor Cruise fundraiser in support of the Angelman syndrome community. Held on Labor Day, this year’s cruise featured nearly 40 tractors that proceeded on a 40-mile trip on Brown County, Kansas roads. With beautiful weather for everyone to enjoy during the whole day, the group took a lunch break at the local Agricultural Museum, where the Brown County Historical Society helped serve a delicious meal for the cruisers—it was so good, there were no leftovers!
This is the ninth year that the Olsen’s have hosted the Tractor Cruise, and collectively have raised more than $25,000 in support of the AS community over the years! The Olsen’s are looking forward to the 10th anniversary Tractor Cruise next year during Labor Day weekend, which will also kick-off at Everest Middle School in Everest, Kansas.
Many thanks to the Olsen’s and their friends, family and supporters for their incredible support of our loved ones with AS!
Click here for more photos of the 2014 Tractor Cruise—it was a fun time had by all!
The Angelman Syndrome Foundation and the lab of Arthur Beaudet, M.D., at Baylor University are inspired and excited to announce that progress is being made in analyzing a possible avenue of treatment for Angelman syndrome.
The research, funded by the Angelman Syndrome Foundation in the organization’s 2011 and 2013 research grant cycles, seeks to find a possible treatment for Angelman syndrome by activating the paternal copy of Ube3a in a mouse model.
Ongoing research and this latest discovery, published in December in PLOS Genetics, have demonstrated the feasibility of activating paternal Ube3a in mice by terminating the transcription of its antisense RNA Ube3a-ATS genetically. In doing this in the AS mouse model, the research team observed restoration of Ube3a expression, improvement of behavioral defects, and reversal of the impaired long-term potentiation. The research team further studied the imprinting mechanisms of Ube3a and proposed a novel transcriptional collision model. These results provide evidence for a key regulatory role of Ube3a-ATS in Angelman syndrome, opening up an exciting possibility of a gene-specific treatment for Angelman syndrome.
“We at Angelman Syndrome Foundation are optimistic about the future of this research, as our ultimate goal is finding viable treatments and a cure for our loved ones with Angelman syndrome,” said Eileen Braun, executive director of the Angelman Syndrome Foundation. “Our Scientific Advisory Committee goes through a rigorous process in evaluating research projects for potential grants, and we are all thrilled with the results coming from the Beaudet lab. We are incredibly appreciative of the Baylor team’s dedication to creating a better future for individuals with Angelman syndrome.”
For more information about the research or the Angelman Syndrome Foundation’s 2013 research grants, please click here.
The Angelman Syndrome Foundation previously supported breakthrough research showing that topoisomerase inhibitors—specifically, topotecan, an FDA-approved drug used in cancer treatments—activates the paternal allele of Ube3a, identifying a possible treatment for Angelman syndrome. The continuation of that research at the University of North Carolina-Chapel Hill has extended the possibility of using topoisomerase inhibitors to treat individuals with Angelman syndrome, and has also identified possible side effects of these drugs on the developing brain. This research is the first to show that topoisomerase inhibitors unsilence Ube3a both in a mouse model and, because of collaborative work with Dr. Stormy Chamberlain at the University of Connecticut, in stem cell-derived neurons from an individual with Angelman syndrome (deletion positive). This study thus demonstrates how Ube3a can be reactivated in patient-derived neurons. The researchers also found that in the process of activating the paternal copy of Ube3a, topotecan reduced the levels of other genes that are linked to autism, which has the potential to result in characteristics of autism in individuals. This research suggests there may be trade-offs in using these drugs to unsilence Ube3a in individuals with Angelman syndrome, and could provide insights into why mutations in topoisomerases are linked to autism. This research also highlights the continued importance of defining a critical treatment window for topoisomerase inhibitors, to determine when these drugs have their best chance of being effective while minimizing side effects on the developing brain. Most importantly, this study highlights the importance of supporting rigorous preclinical research on topoisomerase inhibitors, or any other drugs, prior to advancing into clinical trials for individuals with Angelman syndrome. Access the abstract published in Nature,
Frequently Asked Questions
1. What is Angelman syndrome’s correlation to autism and how are they linked already?
2. How are topoisomerase inhibitors linked to autism?
3. Why is the Angelman Syndrome Foundation funding this research?
4. How could this research impact my individual who has Angelman syndrome, or for my individual who has a dual diagnosis of Angelman syndrome and autism?
5. What are the next steps?
6. If we don’t get a “cure” from this research, then what are we getting from this research?
7. How much did the Angelman Syndrome Foundation fund for this endeavor, and how much will the organization continue to fund?
This study is one of several ASF research initiatives that investigate potential treatments for AS. In addition to exploring topoisomerase inhibitors, the ASF is currently funding research that studies the ability of antisense to awaken the paternal Ube3a gene and the optimal time to administer treatment.
The Angelman Syndrome Foundation (ASF) announced today that because of the generosity of its supporters the organization has awarded $1.25 million to six research grants focused on finding treatments and defining the optimal window for treatment for individuals with Angelman syndrome, a neurodevelopmental disorder which can be similar to autism. ASF leadership approved $250,000 more than the original $1 million call for research proposals earlier this year due to the nature of the research studies and their potential impact on all ongoing Angelman syndrome, autism and other developmental disorder-related research.
“Angelman syndrome research continues to edge closer and closer to potential life-changing treatments and opportunities for individuals with Angelman syndrome, and it is because of the tremendous support of our community that the ASF is able to invest in these important research endeavors that are quintessential to the success of all future AS preclinical and clinical trials,” said Tim McCarty, president of the ASF board of directors. “The ASF’s Scientific Advisory Committee and leadership team have evaluated these research projects thoroughly and are confident in the direction they advance Angelman syndrome research, while also furthering the advancement of related neurodevelopmental disorders including autism. Families, friends, loved ones and others close to individuals with Angelman syndrome who have supported the ASF during our National Walk and other times of the year have made this research investment possible.”
In evaluating this year’s research proposals, the ASF Board of Directors and Scientific Advisory Committee focused on proposals that sought to discover new therapeutics for Angelman syndrome or to better understand the scientific complexities of Angelman syndrome. This year’s Angelman syndrome research grants are significant as they seek to further define the optimal age at which to administer treatment, or the treatment window, and they further test an already FDA-approved drug as being a viable overall treatment for Angelman syndrome.
The breadth and depth of ongoing Angelman syndrome research, which is leading closer towards a cure, makes available the opportunity for this year’s funded research projects to also further the understanding of varying UBE3A gene mutations and deletions, the causative gene in Angelman syndrome. Additionally, this year’s funded research seeks to further understand learning and memory deficits in individuals with Angelman syndrome and how they impact individuals genetically and behaviorally.
“Not all individuals with Angelman syndrome have the same genetic blueprint that causes the symptoms of Angelman syndrome, which is also why our leadership team believed that each of these research projects is important,” said Eileen Braun, executive director of the ASF. “We want to more fully understand and be able to treat what is causing the symptoms of Angelman syndrome in each individual and help improve his or her quality of life. The strides that research in recent years has made sets an excellent stage to build upon and we are optimistic about the direction of this year’s funded research and the further building blocks it will create.”
Research grants were awarded to:
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. As the largest non-governmental funder of Angelman syndrome research, the ASF sponsors Angelman syndrome research through grants to researchers pursuing promising avenues of discovery. Since 1996, the ASF has funded 72 research grants totaling more than $5.8 million. The ASF has awarded a majority of these funds ($5.5 million) beginning in 2005.
Dr. Benjamin Philpot’s lab at the University of North Carolina Chapel Hill continues to make headway in identifying drug compounds that may lead to a viable treatment for Angelman syndrome. As announced on Monday, April 29th from the Simons Foundation Autism Research Initiative, this research has found 30 drug compounds that activate the paternal copy of Ube3a in an Angelman syndrome mouse model. This research is ongoing, and was launched by an ASF-funded research grant to Philpot’s lab in 2011 that resulted in the initial research breakthrough that topoisomerase inhibitors may provide a viable treatment for Angelman syndrome.
The Angelman Syndrome Foundation (ASF) announced today that ASF-funded research has uncovered in more depth how Angelman syndrome, a neurodevelopmental disorder similar to autism, affects specific neurological processes that may be needed for memory and learning. The research, which is being conducted through a scientific collaboration centered at Brown University in Providence, R.I., has also discovered how an existing drug compound may help restore these neurological processes affected by Angelman syndrome.
“I think we are really beginning to understand what is going wrong. That’s what is very exciting,” said John Marshall, professor of medical science in the Department of Molecular Pharmacology, Physiology, and Biotechnology, and the senior author of this research study that was published in the journal PLoS Biology in January 2012. “I am immensely indebted to the ASF for their research funding, as this study would not have been possible without their support.”
The greater understanding of neuronal communication that was revealed with this research project has positive implications for other Angelman syndrome research projects being conducted among other groups, just as other similar research projects assisted this research team in reaching their discovery.
“We at the ASF are inspired by the results of this research collaboration, and we look forward to seeing how it continues to develop and shed further light on the neuronal complexities of Angelman syndrome,” said Tim McCarty, president of the ASF board of directors. “Our goal with all research that we fund is to support initiatives that examine different areas of Angelman syndrome to help broaden the understanding of exactly how Angelman syndrome can be treated. It is broad, multiple-institution support that we believe will help move research faster and closer to a cure.”
Using an Angelman syndrome mouse model, the research team uncovered a signaling breakdown in Angelman syndrome that provides greater clarification about this specific neuronal function of the brain. There are biochemical pathways stimulated in the typically developing brain, which are an important growth factor in learning processes, that are not fully activated in individuals with Angelman syndrome. The research team believes this is what causes specific, yet undetermined, defects in neuronal communication in the Angelman syndrome brain.
The research team also uncovered how an existing drug compound called CN2097, which is believed to also protect neurons under conditions of stroke and in disease states such as multiple sclerosis, can help in correcting the signaling defects in Angelman syndrome. CN2097 is a compound that is unlikely to be used in patients because it breaks down easily within a few hours, meaning that its beneficiary affects may not be long lasting. However, the research team believes it may be possible to alter the chemistry of CN2097 to make it, or some form of it, useful as a treatment.
Read more about this research discovery from Brown University. See more information about ASF-funded research.
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 promising avenues of discovery. Since 1996, the ASF has funded 68 research grants totaling more than $4.8 million. The ASF has awarded a majority of these funds ($4.3 million) beginning in 2005.