It is hard to believe that it has been a year since the Global Angelman Syndrome Registry was launched. This project is now the largest ever Angelman syndrome study to date, with over 450 participants, call us greedy but we want more. There are over 7000 people that “like” the Angelman Today Facebook page, we know that we can increase these numbers drastically and we want to take some time to explain to you why you should care and how your participation can shape Angelman syndrome research right now.
To borrow from Rare Disease advocate Sharon Terry in her Ted talk, “Researchers don’t share. People told us you can’t herd cats. Well, yes you can, if you move their food. DNA and clinical data is the food.”
The story of your individual with Angelman syndrome is extremely powerful, it is even more powerful when combined with stories around the world. Investigators save huge amounts of time in the initial stages of projects without the need to collect information to test questions, get answers and ask more questions. To develop research projects, recruit for clinical trials and even measure their effectiveness. It’s a win-win, researchers don’t need to find funding for investigative work and we don’t have to fundraise for that to happen!
The registry is already working! Research applications and requests to share online studies have been sent to registry participants. FAST has had grant applications where the intended recruitment is through the patient registry which is proof of how valuable a tool this is.
If you grant permission, you can be emailed about participating in online studies, research projects and clinical trials. The people doing this study will NOT be given your name, you will be contacted by the registry curator to ask your consent again first where they will give you contact details or links to find out more.
If you are reading this and saying “ I really should do this one day”, here is a 3 step guide to getting your entry off the ground quickly. (these are only guidelines; you can do this quicker)
- Right now – Visit angelmanregistry.info … what are you waiting for? Click on “Register now” and It will take you two minutes to register for a login. (you do not have to nominate a supervising clinician at this stage, you can do that later)
- Schedule an hour within the week – Make sure you won’t be interrupted, ideally when kids are at school or in bed. Get a notepad and pen. Systematically work through the registry modules. There are a lot of questions, you don’t have to do them all I one hit. When you stumble and can’t remember a date, or its asking to upload results, make a note of what it is so that you can come back in step 3.
- Diarise to hit social media (within 14 days from today). I’m serious! The nature of social media means we often celebrate our children’s achievements, but also their struggles. Grab a pen and write some dates down – milestones, seizures etc. (you might also have a baby book or a file with dates and test results). This should help with the lingering questions you had at step 2. The neurology module is difficult, whilst a lot of us have pseudo degrees in neuroscience the terminology has recently been updated, if you have issues you can contact the registry curator email@example.com (she is based in Australia so depending on the time of the day you may not get an immediate response), or talk with your health professional.
We are aiming to hit 1000 by the end of 2017 – will you help us build this amazing Angelman resource and speed up our journey towards a cure?
Visit angelmanregistry.info to join the project or access the data.
By Sybille Kraft Bellamy
Mother of Maxent, AS 14 years old.
Thirteen years ago in July 2003 Maxent was diagnosed with Angelman syndrome (AS), he was 18 months old.
Today he is a handsome teenager in excellent physical condition with no medical issues. Nevertheless, this was not always the case. From infancy to his toddler age he was chronically sick and he spent more time in the hospital than at home. Very quickly I had the certitude that diet should be the best accessible and fastest way to help him.
Following my own observation and encouraged by Max’s pediatrician (and later by our neurologist), I started paying attention to his diet and removed most of the simple carbohydrates and insisted on replacing them with all kinds of fats.
The change confirmed that my maternal instinct about Max’s incapacity to deal with blood sugar fluctuation was correct.
The low carbohydrate/high fat diet was and will always be his first line of treatment like many other patients with severe disorders.
My confidence and enthusiasm in nutritional therapy is being shared by many parents.
Unexpectedly, a couple of years ago when I was put in contact with Maria Picone (through Gary Taubes) I had an immediate connection. We felt that many of our everyday battles were very similar, and our energy and desire to share our success with the diet with our community was a necessity.
Maria’s daughter, Tea, has Prader-Willi syndrome (PWS). I had the pleasure to meet her in her school with her friends and teachers and I was truly impressed by her personality.
She is a beautiful, smart little girl full of energy and very talkative!
Angelman syndrome and Prader-Willi syndromes were the first imprinted genetic disorders to be described in humans. Both syndromes are associated with loss of the chromosomal region 15q11-13( band 11 of the long arm of the chromosome 15).
This region contains the paternally expressed genes SNRP and NDN and the maternally expressed gene UBE3A.
Paternally inheritance of a deletion of this region is associated with PWS characterized by hypotonia, obesity and hyperphagia. Maternally inheritance of the same deletion is associated with AS (characterized by epilepsy, tremors and sleeping disorders).
In fact, many children with AS present typical characteristics of PWS, like an insatiable appetite and hormonal disorders. Also, some children with PWS suffer from epilepsy, also very common in AS.
It is well-known that patients with AS greatly benefit with therapeutic diets but it appears that patients with PWS do as well.They have better appetite control and a better body muscle mass repartition.The diet is beneficial for both syndromes, on a physical and cognitive aspect.
Many studies around the world confirmed the positive result on the diet with a better control of the epilepsy, however the full extent of the diet with some syndromes is not well-known because of the lack of data.
Patients and their caretakers need a data bank where they can have access to information concerning specific medical protocols and observations from patients and professionals from the medical field.
TREND Community was created to give patients a place to share their stories and contribute real-world data that will inform other patients, clinician, scientists and researchers. It is turning anecdotes into evidence.
TREND Community Initiatives connect its patient communities with leading specialists to collectively evaluate the effectiveness of specific therapies, diet or other environmental interventions. The Angelman Syndrome Diet Initiative is the first initiative for the Angelman community.
The AS Diet Initiative will introduce a group of individuals with AS to a pre-ketogenic diet and track patient-reported outcome measures hunger, cognition, behavior, energy, body composition and quality of life. This specific investigation of AS ketogenic diets is a wonderful opportunity to bring new hope for many patients and their families.
The diet Initiative will be carried out under the guidance of Beth Zupec-Kania, RDN from the renowned Charlie Foundation.
I will have the pleasure to bring my expertise of Angelman syndrome and diets. I will share all the positives outcomes I obtained with LGIT/MCT but also provide caution and reminders that this is a medical diet and must be done under the supervision of your doctor.
The AS Diet Initiative is sponsored by Gary Taubes, co-Founder and Director of Nutrition Science Initiative (NuSi), and Robert Goldstein.
We are extremely thankful to Gary Taubes and his ongoing support to help us spread awareness of the wonderful effect of the diet on our children health.
If you would like to learn more about AS Diet Initiative or request an invitation to join send an email to firstname.lastname@example.org
For more information visit www.angelmanalliance.org
You can read more about Angelman Syndrome on :
From Bergamo to Rotterdam: Studying Angelman syndrome.
Associazione Angelman Onlus is financing a four year research grant of 120 000euro.
The Italian Associazione Angelman Onlus, based in Bergamo, is financing the grant of a doctorate student’s research into the syndrome of Angelman.
The funding will last four years.
Monica Sonzogni, a young Italian molecular biologist will work at the Erasmus MC in Rotterdam under the supervision of Prof. Ype Elgersma.
Associazione Angelman Onlus will fund 30 000 euro (120 000 euro in total) which will finance the study.
This will be coordinated together with the Research Foundation of the Ospedale Papa Giovanni XXIII in Bergamo.
The research grant is also supported by the Rotary Club of Treviglio and Pianura Bergamasca.
Associazione Angelman Onlus, founded in Lombardy in 2012 , was the initiative of a family with two main objectives: bringing Angelman Syndrome to public attention as well as that of the pharmaceutical industry and helping to support the genetic research into Angelman Syndrome.
ASF-funded research, published in Nature, proves paternal Ube3a can be activated and AS symptoms can be recovered.
Dr. Art Beaudet
Promising Angelman syndrome research continues to move closer toward potential clinical trials, as announced in December in a paper in Nature by Dr. Art Beaudet and his research team at Baylor College of Medicine (BCM).
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.
The Angelman Syndrome Foundation 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. The BCM Intellectual and Developmental Disability Research Core grant and the National Institutes of Health were also major funders of this research.
Dan Harvey, ASF Scientific Advisory Committee Chair, has provided the following summary about the research.
Neurotypical individuals have two versions of the AS 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 AS, 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 AS. The studies described in this article for Nature are the culmination of those efforts.
Awakening the gene
Recent studies by Dr. Ben Philpot and colleagues at the University of North Carolina-Chapel Hill 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.
Treatment and recovery
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 known 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.
Conclusion and next steps
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 next step is to conduct more testing to determine exactly how the cognitive deficits associated with AS are recovered.
A Family’s Perspective
Provided by Debra F. Sukin, mother of Jacob Sukin, who is 13 years old
Jacob is deletion positive for Angelman syndrome and was first diagnosed at Texas Children’s Hospital with genetic testing in Dr. Beaudet’s lab back in 2001. Jacob’s diagnosis was devastating to our family as we learned about Angelman syndrome’s physical and mental challenges and limitations.
While seeking the best care and treatment for Jacob to maximize his potential each year, our family set out to learn what research was available, educate others on the need for research for this rare genetic syndrome, and raise funds for research.
We are thrilled with the recent research findings by Dr. Beaudet and the genetics lab at BCM at the Jan and Dan Duncan Texas Children’s NRI that was published in Nature magazine. The ability to promote the silent paternal gene in the AS mouse model and witness normalization of behavioral and learning characteristics as well as elimination of seizures and ataxia provides hope.
Jacob has a long life expectancy. Any therapeutic intervention that will improve his ability to live in this world or create a cure is exactly why we believe in research. We are so grateful to the Angelman Syndrome Foundation who funded this research along with Baylor and TCH.
Professor David Segal heads a research laboratory at The Genome Center of the University of California Davis. A main focus of the Segal Lab is designing proteins that can bind to DNA and “turn on” or “turn off” the expression of specific genes. Such DNA binding proteins have the potential to be used in applications such as targeted gene expression therapy for conditions with a known genetic basis. For example this approach might allow people with Angelman Syndrome to make up for the loss or inactivation of the UBE3A gene on the chromosome inherited from the mother, by “turning on” or expressing the UBE3A gene inherited from the father.
Professor Segal recently co-authored a review article in BMC Neuroscience* entitled The prospect of molecular therapy for Angelman syndrome and other monogenic neurologic disorders. The article discusses the use of DNA-binding proteins called artificial transcription factors as potential treatments for Angelman Syndrome. We asked Professor Segal about the technologies described in the review and the implications they could have for people with Angelman Syndrome.
What is targeted gene expression therapy?
In some types of genetic disease, there are genes that we would either like to turn on or turn off in order to treat the disease. Unfortunately, drugs don’t do this very well. Drugs are good at inhibiting enzymes that carry out chemical reactions in the cell, or binding to receptors on the cell’s surface to block signaling pathways. They usually cannot turn on specific genes. There are also some drugs that act on the general machinery that regulates gene expression. That would be “untargeted” gene expression therapy, because these drugs affect the expression of many genes. My lab believes that if you want to turn specific genes on or off, you should try to understand how nature does this. Nature uses proteins called transcription factors that bind to specific sequences of DNA. In this way, the transcription factors activate or repress just their target gene. We are trying to adopt this same approach to create a “targeted” gene expression therapy for Angelman Syndrome.
Why would Angelman Syndrome be a suitable condition to be treated using targeted gene expression therapy?
Angelman Syndrome is caused by loss of expression of the UBE3A gene in the brain which means that the UBE3A protein it codes for is not made. Regulation of UBE3A expression in the brain is unusually complex and the loss of expression can be due to several different types of mutations or errors that occur where UBE3A is located on the maternal chromosome, the chromosome a child inherits from the mother. However, in all cases there is a perfectly good copy of the UBE3A gene on the paternal chromosome, which is inherited from the father. In the brain this copy is normally “silenced” by the expression of yet another gene, called the UBE3A-antisense transcript. UBE3A and the UBE3A-antisense transcript lie in the path of each other, like two trains heading towards each other on the same track. Usually the UBE3A gene is the loser in this contest, so it doesn’t get to make its protein because its path is blocked by expression of UBE3A-antisense transcript. If we can either turn the UBE3A gene on stronger, so that it is more likely the winner, or if we could turn the UBE3A-antisense transcript down, so that it is more likely the loser, we may be able to restore UBE3A expression in the brain. It is worth mentioning that most other genetic diseases have both copies (maternal and paternal) of the gene mutated, and thus it doesn’t help to turn those genes up or down. In this case, the unusual gene regulation in the region of the UBE3A gene gives us a special opportunity for targeted gene therapy.
The use of artificial transcription factors for targeted gene expression therapy is discussed in your article. What are artificial transcription factors?
Transcription factors are one of the main tools that nature uses to turn genes on or off. They are proteins that are typically composed of two parts. One part is called an effector domain, which interacts with other proteins in the cell to cause the gene to be turned on or off. The other part is a DNA-binding domain, which can seek out and bind to a specific sequence of DNA and thus bring the effector domain to a specific gene. To make an artificial transcription factor, we steal an effector domain of a natural transcription factor and attach it to a programmable DNA-binding domain. A lot of scientific research has gone into how to make high quality programmable DNA-binding domains, and they are improving all the time. They go by names such as zinc fingers, TALEs and CRISPRs. The result is an artificial transcription factor that can turn on or off whatever gene to which we program it, in the case of Angelman Syndrome this is either UBE3A or the UBE3A-antisense transcript.
What advantages do you think they will have over other molecules being used or developed for gene therapy?
This approach should regulate the gene where it naturally occurs on the chromosome, and there may be some advantages to that. There is a lot about gene regulation that we don’t fully understand. For example, the UBE3A gene actually produces at least three slightly different forms of the UBE3A protein depending on variations in the process that converts the gene sequence into the protein it codes for. Although we think they are all doing pretty much the same thing, some forms of UBE3A protein end up in the cell nucleus and others in different parts of the cell. A traditional gene therapy would introduce a new healthy copy of the gene in a viral vector (a sequence of modified virus DNA) that expresses the gene using its own machinery. Using this method only one form of the protein would be made. Our method uses the cells normal machinery and would allow all the natural forms to be made.
Another important lesson we have learned about gene therapy is that dosage matters. Too little gene expression can be bad, but too much can be bad too. For example too much UBE3A expression has been associated with autism. Our approach may offer the ability to tailor the dose of gene expression to the individual, kind of like drug therapies do.
There are other kinds of therapies that target the chromosomal copy of UBE3A or the UBE3A-antisense transcript, such as the antisense oligonucleotide therapy being pioneered by Dr. Arthur Beaudet¹ at the Baylor College of Medicine. That method uses short, man made sequences of nucleic acids, the building blocks of DNA, to block the expression of specific genes by preventing their proteins being made. It may have similar advantages or different advantages to artificial transcription factors. Ultimately, several methods may be useful, or one method may prove to be much more effective than the others, we will just have to see. In any case, testing several strategies ensures that the Angelman community is always the winner, because they will know that whatever proves most useful will be the best that all of us can do, not just the best that one person can do.
¹ Editor’s note: Dr.Beaudet’s antisense oligo approach aims to block the UBE3A-antisense transcript and allow for expression of paternal UBE3A.
Will it be possible to deliver artificial transcription factor therapeutics to specific areas of the brain that are affected in Angelman Syndrome?
Our current understanding is that UBE3A expression is lost throughout the brain in Angelman Syndrome. Our preliminary data suggests our artificial transcription factors can become widely distributed in the brain, much more so than any viral vector in use today. However, delivery remains an active area of research for this project, and we will continue to make improvements and incorporate the improvements of others to do the best we can with this.
Do you think this type of therapy could offer a treatment for all of the symptoms of Angelman Syndrome?
I don’t think anybody really knows if restoring UBE3A to full activity will fix all the symptoms of Angelman Syndrome. About 70% of affected individuals have a large deletion that removes other genes besides UBE3A. Even though there is still one copy of these genes on the paternal chromosome that is active (unlike the paternal UBE3A, which is silenced), the loss of even one copy of these genes from the maternal chromosome may contribute to some of the neurologic symptoms of Angelman Syndrome. Experiments to understand this better are in progress, and this is just one more thing that we still have to learn.
Are there likely to be any side effects to this kind of therapy?
Since our artificial transcription factor does not normally exist in nature, we are always concerned about an immune response against it. This would probably not cause harmful side effects but could reduce its effectiveness. Also, like drugs, there could be “off-target” effects if the factor were to regulate other genes unintentionally. The issue of side effects is something that we really want to understand before we think about any trials in humans.
How long could it take before we know whether they might be suitable as a treatment for humans?
The researchers and the whole Angelman community are lucky to have two very well funded sources of support in the Angelman Syndrome Foundation and the Foundation for Angelman Syndrome Therapeutics. My work is mostly funded by the latter, and they are very serious about moving things quickly into something that can help people. But, to paraphrase Einstein, science should move as quick as possible, but not quicker. We need to better understand side effects and immune response. We need to examine different dosing regimens and delivery methods. Unfortunately these experiments take time to do correctly. So I can’t make any promises about when we will be ready for clinical trials, I can only promise that I will keep trying.
Can you tell us anything else about the research into Angelman Syndrome that your lab has been doing and how it is progressing?
We have been developing artificial transcription factors for targeted gene expression therapy of Ube3a in a mouse model of Angelman Syndrome. The factors are based on DNA binding proteins known as zinc finger proteins which recognize and target specific areas of DNA. The factor was designed to turn the Ube3a -antisense transcript down on the paternal chromosome, which we hoped would restore Ube3a expression in the brain. Our preliminary data suggests that we are able to inject this purified factor into mice and it is indeed able to activate expression of UBE3A in the mice brains. This is a very exciting result for us for several reasons. Most injected proteins as well as many drugs are not able to cross the blood-brain barrier, a membrane of tightly packed cells that protects the brain from foreign substances in the blood. However, our engineered protein seems able to get in. It also seems to activate the Ube3a gene, and by using a special antibody that binds to the area of interest we are fairly convinced that it is the silenced paternal copy that is getting turned on. I say “seems” and “suggests” because we have not published these findings yet, which means our work has not been peer reviewed by other scientists. We want, and the community should also want, that everyone can look at our work and agree that it is true. As a scientist I need to be the biggest skeptic of my own work, and part of that is carefully building proof that what we think is happening is actually happening. We hope to publish the first chapter of our story soon.
However, there will be more chapters because there are still many things we need to learn before we can think about trying to activate UBE3A in a person. We need to understand the potential side effects of our treatment, and if any genes besides UBE3A are affected. We need to know how long the activation lasts after treatment. And of course we need to know what affect this treatment has on the behavior of the Angelman mouse. All those studies are also in progress right now. One of the things that we and others have been learning is that the symptoms that our mouse model of Angelman Syndrome display is a lot milder than what we typically see in people. We have some ideas about why that might be, and with the help of the Foundation for Angelman Syndrome Therapeutics (FAST), we are building better rodent models of the disease. If successful, these new models will help us and the rest of the research community to test drugs and develop new targeted therapies. I think the advances that have been made in just the past few years, Dr. Ben Philpot’s discovery of a Ube3a-activating drug, Dr. Ed Weeber’s gene therapy experiments restoring Ube3a expression in mice, and Dr. Art Beaudet’s antisense termination experiments and oligonuclotide therapy, are all very exciting and certainly seem to offer hope for better treatments. I have certainly been inspired by their work and the work and support of the broader Angelman Syndrome community, and I am glad to think that I might be able to contribute to that.
* Bailus and Segal: The prospect of molecular therapy for Angelman syndrome and other monogenic neurologic disorders. BMC Neuroscience 2014 15:76.