Results of a new study by a team of researchers at the University of North Carolina at Chapel Hill may help pave the way to a treatment for Angelman syndrome, a neurogenetic disorder for which there is currently no effective therapy.
The most characteristic feature of AS is the absence or near absence of speech throughout the person’s life. The disease, often misdiagnosed as cerebral palsy or autism, is caused by mutations or deletions in the Ube3a gene inherited from the mother, or the maternal allele. The Ube3a protein produced by that gene is a key component of an important molecular pathway that helps brain neurons pass electrical or chemical signals to other neurons via the synapse.
There is a paternal Ube3a allele, but whereas both the maternal and paternal alleles are expressed in most body tissues, this gene is dormant in human and rodent neurons.
“We wanted to determine if there could be a way to awaken the dormant allele and restore Ube3a expression in neurons,” says neuroscientist Benjamin D. Philpot, PhD, one of three senior investigators in the study and an associate professor of cell and molecular physiology at the UNC School of Medicine.
In a paper published online December 21 in the journal Nature, the team of UNC scientists, which included researchers from the UNC Eshelman School of Pharmacy, says it has found a way to awaken the paternal Ube3a allele, opening the door to a potential treatment strategy for AS.
Using a library of FDA-approved drugs, the UNC team discovered that irinotecan, a topoisomerase inhibitor known to be active in the central nervous system, robustly awakened Ube3a in genetically engineered mice. Subsequently, the team found that the medication topotecan and several other topoisomerase inhibitors can also awaken Ube3a.
Importantly, the protein from the awakened paternal Ube3a was functional and was expressed by the gene in amounts comparable to that of normal maternal Ube3a in control animals.
The researchers determined that topotecan awakened the dormant paternal Ube3a allele by reducing antisense RNA, a strand of ribonucleic acid that silences the allele.
The study is “the first example of a drug that regulates antisense RNA and, as a result, regulates protein levels of a coding gene,” says neuroscientist Mark J. Zylka, PhD, one of the study’s senior coauthors and an assistant professor of cell and molecular physiology.
Zylka and Philpot caution against using topoisomerase inhibitors right now to treat AS, given the limits of current knowledge.
“We’d like to stress that these compounds are not ready to be used clinically for Angelman syndrome,” Zylka says. “We don’t know what the off-target effects might be on a gene or genes with similar DNA sequences. We need to figure out optimal concentrations and dosing before we move to clinical trials. And we need to determine which drug is best.”
The other senior coauthor on the study is Bryan Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology and Translational Proteomics, director of the National Institute of Mental Health Psychoactive Drug Screening Program, and a professor in the UNC Eshelman School of Pharmacy. Jian Jin, PhD, the associate director of medicinal chemistry at the Center for Integrative Chemical Biology and Drug Discovery, was also on the team of researchers.
Other UNC coauthors are: Hsien-Sung Huang, John A. Allen, Angela M. Mabb, Ian F. King, Jayalakshmi Miriyala, Bonnie Taylor-Blake, Noah Sciaky, J. Walter Dutton Jr., Hyeong-Min Lee, Xin Chen, and Arlene S. Bridges.
The research was supported in part by funds from the Angelman Syndrome Foundation, the Simons Foundation, the National Institute of Mental Health, the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the NIMH Psychoactive Drug Screening Program, and the NC TraCS Institute funded by the NIH Clinical and Translational Science Awards (CTSA).