|
Results of a new study from the University of North Carolina atChapel Hill may help pave the way to a treatment for a neurogeneticdisorder often misdiagnosed as cerebral palsy or autism . Known as Angelman syndrome, or AS, its most characteristic featureis the absence or near absence of speech throughout the person'slife. Occurring in one in 15,000 live births, other AScharacteristics include intellectual and developmental delay,severe intellectual disability, seizures, sleep disturbance, motorand balance disorders. Individuals with the syndrome typically havea happy, excitable demeanor with frequent smiling, laughter, andhand flapping. No effective therapies exist for AS, which arises from mutations ordeletions of the gene Ube3a on chromosome 15. The Ube3a proteinproduced by the gene is a key component of a molecular pathway thatis very important to all cells, especially brain neurons by helpingthem pass electrical or chemical signals to other neurons via thesynapse. Angelman syndrome is linked to mutations or deletions in the Ube3agene inherited from the mother; thus, the maternal allele. In mosttissues of the body, both the maternal and paternal alleles areexpressed. But in rodents and humans, the paternal Ube3a allele isintact but silent, or dormant. What apparently accounts for the dormancy of that allele is astrand of ribonucleic acid known as antisense RNA, which in termsof gene expression keeps paternal Ube3a silenced, or off. Oncereferred to as the genome's "dark matter," antisense RNA makes nofunctioning gene product, but works to repress expression ofanother gene by binding to its RNA. "We wanted to determine if there could be a way to "awaken" thedormant allele and restore Ube3a expression in neurons," saidneuroscientist Benjamin D. Philpot, PhD, associate professor ofcell and molecular physiology, one of three senior investigators inthe study and a member of the UNC Neuroscience Center. In a report of the research published online Dec. 21,2011 in thejournal Nature, the interdisciplinary team of UNC scientists saythey have found a way to "awaken" the paternal allele of Ube3a,which could lead to a potential treatment strategy for AS. "We have taken advantage of a tool that allows us to distinguishbetween active and inactive alleles," Philpot said. "That tool is amodified mouse that's engineered so that the Ube3a gene has afluorescent 'reporter' gene attached to it, which tells you whenthe gene is on or when it's off. When the gene is on, neurons willfluoresce in yellow, but won't when the gene is off." Other 'tools' available on the UNC campus come from study seniorauthor Bryan L. Roth, MD, PhD, Michael Hooker DistinguishedProfessor of Pharmacology and Translational Proteomics and directorof the National Institute of Mental Health Psychoactive DrugScreening Program. These include highly automated robotics of thesort normally found in major pharmaceutical companies: fluidhandling robotics and automated high-content imaging that combinethe molecular tools of modern cell biology with automated highresolution microscopy and robotic handling (see pdspdb.unc.edu/download/robotLab2011.php ). Using a library of FDA-approved drugs obtained from the NationalInstitute of Health (the NIH Clinical Collection) the UNC teamdiscovered that irinotecan, a topoisomerase (TOPO-EYE-SOM-ERASE)inhibitor known to be active in the central nervous system --robustly 'awakened' Ube3a. Subsequently, the team identified theFDA approved medication topotecan and several other topoisomeraseinhibitors as drugs which can 'awaken' Ube3a. "When we gave topotecan to these neurons they would now glow,indicating that the paternal allele was now on," Philpot said.Topotecan apparently awakened the dormant Ube3a allele bydown-regulating, or reducing, antisense RNA in the paternal copy ofUbe3a, the researchers determined. When topotecan was given to the genetically engineered mice, "itunsilenced the paternal Ube3a allele in several regions of thenervous system, including neurons in several areas of the brain andin the spinal cord," the authors state. These findings also heldtrue for irinotecan. Importantly, the protein from the unsilenced paternal Ube3a wasfunctional and was expressed by the gene in amounts comparable tothat of normal maternal Ube3a in 'control' animals. The study's third senior co-author, neuroscientist Mark J, Zylka,PhD, assistant professor of cell and molecular physiology and a UNCNeuroscience Center member says the study is "the first example ofa drug that regulates antisense RNA and, as a result, regulates[protein] levels of a coding gene." According to Philpot, the increased scientific interest in Ube3a isbecause certain DNA copies, or duplications, in maternal chromosome15 are associated with classic forms of autism. "If you have toolittle Ube3a you have Angelman syndrome. If the maternal allele isduplicated, it might be a contributing factor to autism." Zylka and Philpot caution against using topoisomerase inhibitorsnow to treat Angelman syndrome, given the limits of currentknowledge. "We'd like to stress that these compounds are not ready to be used clinically forAngelman syndrome," Zylka said. "We don't know what the off-targeteffects might be on a gene or genes with similar DNA sequences. Weneed to figure out optimal concentrations and dosing before we moveto clinical trials. And we need to determine which drug is best." For people to use these drugs now for Angelman syndrome, withoutfurther preclinical studies, might be a health risk, Philpot adds,"one that could jeopardize successfully bringing these compounds toclinical trials." Along with Philpot, Zylka and Roth, coauthors from UNC wereHsien-Sung Huang, John A. Allen, Angela M. Mabb, Ian F. King,Jayalakshmi Miriyala, Bonnie Taylor-Blake, Noah Sciaky, J. WalterDutton Jr, Hyeong-Min Lee, Xin Chen, Jian Jin, and Arlene S.Bridges. The research was supported in part by funds from the AngelmanSyndrome Foundation, the Simons Foundation, the National Instituteof Mental Health, the National Eye Institute, the NationalInstitute of Neurological Disorders and Stroke, the NIMHPsychoactive Drug Screening Program, and NC TraCS Institute fundedby the NIH Clinical and Translational Science Awards (CTSA). Additional References Citations. The e-commerce company in China offers quality products such as E-Light Skin Rejuvenation Manufacturer , China 808nm Diode Laser Hair Removal, and more. For more , please visit IPL Beauty Equipment today!
Related Articles -
E-Light Skin Rejuvenation Manufacturer, China 808nm Diode Laser Hair Removal,
|
