美国北加州大学医学院的Benjamin Philpot等人近日《自然》（Nature）杂志发表论文称，抗肿瘤药拓扑异构酶I抑制剂可激活一个沉默的名为Ube3a的父性等位基因，该发现将有利于治疗安琪儿综合征。
安琪儿综合征（或称天使人综合征）在1965年被首次描述，其特点为跳跃式运动、抽搐、学习障碍、及频繁发笑，约每15000名新生儿中便可出现一名安琪儿综合征患儿。而现有的治疗手段都只是对症治疗，无法从根本上改变患者的生存状况。
UBE3A 基因负责编码UBE3A 蛋白，该蛋白在调节非必须蛋白的降解和神经系统的发育中起重要作用。正常人体内有该基因的母性和父性等位基因，在发育过程中父性等位基因被关闭，仅有母性等位基因表达并参与上述调节过程。而在安琪儿综合征患者体内，该基因的母性等位基因发生突变或缺失，导致其无法产生UBE3A蛋白。
因此Benjamin Philpot和Mark Zylka等设计了实验来研究如果UBE3A的父性等位基因被激活，是否会产生UBE3A蛋白质，从而达到治疗安琪儿综合征的目的。
在试验了约2300余种化合物后，研究者发现抗肿瘤药拓扑异构酶I抑制剂可激活该基因。拓扑异构酶在DNA复制期间结合于DNA分子，以帮助其复制，拓扑异构酶抑制剂可抑制拓扑异构酶与DNA分子的分离，最终破坏该DNA。
该药物激活父性Ube3a等位基因的机制尚不明确，但研究者指出，该作用或许与拓扑异构酶I抑制剂可降低反转录基因Ube3a-ATS的表达有关，该反转录基因可阻断Ube3a基因的表达。
随后，研究者给小鼠注射了一种拓扑异构酶I抑制剂--拓扑替康，并观察Ube3a基因在该小鼠神经细胞中的表达。结果发现该父性等位基因被激活，并持续了长达12周的时间。
作者称，该发现或将为安琪儿综合征及其他一些神经发育性疾病的治疗带来新的希望。（生物谷bioon.com）
doi:10.1038/nature10726
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Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons
Hsien-Sung Huang, John A. Allen, Angela M. Mabb, Ian F. King, Jayalakshmi Miriyala, Bonnie Taylor-Blake, Noah Sciaky, J. Walter Dutton, Hyeong-Min Lee, Xin Chen, Jian Jin, Arlene S. Bridges, Mark J. Zylka, Bryan L. Roth & Benjamin D. Philpot.
Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A (UBE3A)1, 2, 3. In neurons, the paternal allele of UBE3A is intact but epigenetically silenced4, 5, 6, raising the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein7, 8. Using an unbiased, high-content screen in primary cortical neurons from mice, we identify twelve topoisomerase I inhibitors and four topoisomerase II inhibitors that unsilence the paternal Ube3a allele. These drugs included topotecan, irinotecan, etoposide and dexrazoxane (ICRF-187). At nanomolar concentrations, topotecan upregulated catalytically active UBE3A in neurons from maternal Ube3a-null mice. Topotecan concomitantly downregulated expression of the Ube3a antisense transcript that overlaps the paternal copy of Ube3a9, 10, 11. These results indicate that topotecan unsilences Ube3a in cis by reducing transcription of an imprinted antisense RNA. When administered in vivo, topotecan unsilenced the paternal Ube3a allele in several regions of the nervous system, including neurons in the hippocampus, neocortex, striatum, cerebellum and spinal cord. Paternal expression of Ube3a remained elevated in a subset of spinal cord neurons for at least 12?weeks after cessation of topotecan treatment, indicating that transient topoisomerase inhibition can have enduring effects on gene expression. Although potential off-target effects remain to be investigated, our findings suggest a therapeutic strategy for reactivating the functional but dormant allele of Ube3a in patients with Angelman syndrome.
