Research on Topoisomerase Inhibitors
University of North Carolina-Chapel Hill Research Overview and Frequently Asked Questions
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?
- While some doctors, scientists and researchers do and some do not consider Angelman syndrome to be an Autism Spectrum Disorder (ASD), all can agree that there is, to a certain extent, a connection between the two. What is known so far is that:
- Not enough or improper function of the Ube3a gene = Angelman syndrome
- Too much functionality of the Ube3a gene = ASD
- A few developmental and behavioral characteristics do overlap between Angelman syndrome and ASD, yet the main behavioral differentiator is that individuals with Angelman syndrome do not feel the extreme aversion to social situations as do individuals with ASD.
- Individuals with Angelman syndrome are able to read facial expressions, body language and vocal intonations extremely well, and as a result, they enjoy and seek out social interaction.
2. How are topoisomerase inhibitors linked to autism?
- Topoisomerase inhibitors activate the paternal copy of the Ube3a gene but in doing so, they also reduce the levels of other genes linked to autism. It is currently unknown if this could result in characteristics of autism in individuals. With proper timing, it may be possible to activate Ube3a while minimizing side effects associated with reducing the levels of genes linked to autism.
- The effects on autism genes were only present for as long as the topoisomerase inhibitors were present; once the drug wore-off, gene expression returned to baseline levels. However, it is important to note that mutations in topoisomerases have surfaced in some individuals with autism, suggesting that an alteration in the activity of these enzymes increases the risk for autism. This further suggests it may be possible to time drug administration to minimize side effects during critical periods of brain development.
3. Why is the Angelman Syndrome Foundation funding this research?
- The Angelman Syndrome Foundation was the first to fund this pioneering research at UNC in 2009. This research identified 16 different topoisomerase inhibitors that could unsilence paternal Ube3a, making these the first potential treatments for Angelman syndrome. This was also the first research to show that the paternal Ube3a could be unsilenced, paving the way for all future efforts to reactivate this gene that is linked to Angelman syndrome.
- As the research study continued to progress and illustrate promising results, UNC applied for funding to continue the research, and the Angelman Syndrome Foundation awarded a research grant for its continuation (in addition to other organizations providing funding as well).
- The Angelman Syndrome Foundation will continue to fund this research as part of its 2013 research grant cycle to determine the treatment window and autism-related side affects of topoisomerase inhibitors as a potential treatment for Angelman syndrome.
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?
- Currently, topoisomerase inhibitors, while having shown potential, are not currently used to treat individuals with Angelman syndrome. As with any new or repurposed drug, extensive preclinical and clinical work must be done to establish safety and efficacy.
- This research is still in pre-clinical phase and more work is being done before it has the potential to move to a clinical trial.
5. What are the next steps?
- The research team is currently identifying the potential critical window for treatment, and what factors are involved within that critical window: identifying when topoisomerase inhibitors have their best chance of being effective, and if and when topoisomerase inhibition increases susceptibility to autism.
6. If we don’t get a “cure” from this research, then what are we getting from this research?
- This research provides the first evidence that a drug can be used to turn on the paternal copy of Ube3a. Restoring Ube3a levels represents a critical path towards any cure or treatment for Angelman syndrome. Prior to this research, most would have thought it impossible to reactivate a silenced gene. Angelman Syndrome Foundation-funded research has shown that the impossible can be done, by supporting rigorous science and scientists who are truly committed to helping individuals with Angelman syndrome.
- This research has spurred many other investigators to identify additional drugs that reactivate Ube3a, including promising work with antisense oligonucleotides that specifically target the antisense transcript that topoisomerase inhibitors regulate. As with topoisomerase inhibitors, there will likely be the need for numerous studies that define the optimal treatment window to ensure the drugs reach their intended target in the brain.
- This research is beneficial to the overall Angelman syndrome community because it has identified possible side effects from using topoisomerase as a potential treatment for Angelman syndrome before this moves to clinical trial.
7. How much did the Angelman Syndrome Foundation fund for this endeavor, and how much will the organization continue to fund?
- The Angelman Syndrome Foundation originally funded $199,972 for the initial research project in 2009.
- UNC applied for continued funding for this project in 2011 and received $510,000 collectively in funding from the ASF’s 2011 Research Grants. These funds were awarded in two two-year grants of $200,000 each to Dr. Mark Zylka and Dr. Ben Philpot, with an additional $110,000 awarded to Dr. Ian King as part of the Angelman Syndrome Foundation’s Joseph E. Wagstaff Postdoctoral Fellowship.
- UNC applied again in 2013 to continue this promising research, and the Angelman Syndrome Foundation continued to fund this research as part of its 2013 research grant cycle to determine the treatment window and the possible side affects of using topoisomerase inhibitors as a potential treatment for AS. These funds were awarded in two two-year grants of $200,000 each to Dr. Mark Zylka and Dr. Ben Philpot, with an additional $110,000 awarded to Dr. Angela Mabb as part of the Angelman Syndrome Foundation’s Joseph E. Wagstaff Postdoctoral Fellowship.
- If UNC decides to apply for the ASF’s 2014 research grants for additional funds for this or other AS-related research, the ASF would evaluate that research proposal at that time.
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.