Frequently Asked Questions about UNC Angelman Syndrome Research
UNC researchers recently found that topoisomerase inhibitors activate the dormant allele of UBE3A. What does this mean for my family member with Angelman syndrome? Because Angelman syndrome is caused by the loss of the maternally-inherited copy of the UBE3A gene, the discovery that the dormant (paternally-inherited) copy of the UBE3A gene can be activated by a drug suggests a new direction for research on a potential drug therapy for Angelman syndrome. This exciting discovery was published online in Nature on December 21st, 2011 (
see Nature paper).
What are topoisomerase inhibitors? Topoisomerase inhibitors interfere with DNA replication. Several of these inhibitors are FDA-approved for treating certain forms of cancer. This new research indicates these drugs may have additional uses and functions in the brain.
How did you make your discovery? We tested over 2,000 drugs for their ability to unsilence paternal UBE3A in mouse neurons. Each drug was rigorously tested at least four times, and effective compounds were tested many more times. Given that Angelman syndrome is associated with genomic imprinting, we were initially surprised to find that drugs that modify the “epigenome” (e.g. – Histone deacetylase inhibitors, chromatin-remodeling drugs, and DNA methyltransferase inhbitors) did not work (
see supplemental data in Nature paper). Instead, our research uncovered topoisomerase inhibitors as a class of drugs that were capable of unsilencing paternal UBE3A.
I have a family member with Angelman syndrome. Should I have them treated with topoisomerase inhibitors? These drugs are NOT indicated for the clinical treatment of Angelman syndrome, and we advise you do not use these drugs to treat individuals with Angelman syndrome at this time. At the minimum, controlled clinical trials must first be completed to determine if these drugs are safe and effective in patients, particularly if administered long-term. The clinical effects and potential side effects of these drugs for people with Angelman syndrome are not yet known. Moreover, we do not yet know what route will be most effective for drug delivery (for example, oral, intravenous, or intrathecal). Ongoing preclinical studies are being performed to address these issues.
In searching the web I noticed there are additional drugs classified as topoisomerase inhibitors (for example, resveratrol)? We tested this compound (see supplemental table in Nature paper) and found that it does not unsilence the dormant UBE3A allele.
Will there be a clinical trial using topoisomerase inhibitors to treat Angelman syndrome, and if so, can I enter my family member with Angelman syndrome in the trial? The goal of our research is to initiate a clinical trial that takes full advantage of our published and unpublished (proprietary) data. If you are interested in learning more about a future clinical trial, as well as learning more about our current clinic services, please
see the CIDD Angelman Syndrome Clinic website.
How do I register interest in a clinical trial for Angelman syndrome at UNC? You can register interest for a future clinical trial through the
CIDD Angelman Syndrome Clinic website.
Other clinical services for Angelman Syndrome: The CIDD Angelman Syndrome Clinic brings together a multidisciplinary team of clinicians into one setting to address the complex medical and psycho-educational needs of individuals with Angelman syndrome. Information on this clinic can be found at (
http://www.cidd.unc.edu/Angelman-Syndrome/). Please contact the clinic to check their availability. You can contact the CIDD Angelman Syndrome Clinic directly by calling Christie Turcott at (919) 966-2074. Other information on Angelman Syndrome in general and on other services and research is available through the Angelman Syndrome Foundation (
www.angelman.org).