Small Molecule Therapeutic Discovery for Angelman Syndrome

项目总结 Angelman综合征是一种由母体UBE3A等位基因缺失引起的严重神经发育障碍。 在神经元中，UBE3A的父系等位基因在表观遗传上是沉默的。解沉默UBE3A的父系等位基因 为治疗安杰曼综合征提供了一个潜在的变革性机会。我们最近发现了一个小的 在培养的Angelman综合征模型神经元中消除父等位基因UBE3A的分子 小鼠或来自Angelman综合症患者的干细胞。当以非侵入性方式交付给 Angelman综合征模型小鼠，这种小分子导致全脑神经元UBE3A蛋白表达 没有明显的毒性。我们假设我们的小分子方法可以逆转安吉尔曼 小鼠的症状表型，证明其在进一步的安全性研究和未来的临床试验方面的进展是合理的。 为了开发这种方法作为一种治疗Angelman综合征的非侵入性治疗方法，我们建议(1) 建立拯救Angelman综合征模型小鼠的行为和电生理表型，(2) 确定我们的小分子产生父亲UBE3A非沉默的作用机制，以及(3) 进行结构-活性-关系研究，以提高疗效并最大限度地发挥有利的药理作用。通过 推进安吉尔曼综合征的首个小分子治疗，这项研究可能会导致治疗成果 为这些患者群体带来深远的终生利益。

PROJECT SUMMARY Angelman syndrome is a severe neurodevelopmental disorder caused by maternal allele deletions of UBE3A. In neurons, the paternal allele of UBE3A is epigenetically silenced. Unsilencing the paternal allele of UBE3A offers a potentially transformative opportunity for treating Angelman syndrome. We recently discovered a small molecule that unsilences the paternal allele of UBE3A in neurons cultured from Angelman syndrome model mice or from stem cells derived from Angelman syndrome individuals. When delivered noninvasively to Angelman syndrome model mice, this small molecule leads to brain-wide neuronal UBE3A protein expression without observable toxicity. We hypothesize that our small molecule approach can reverse Angelman syndrome phenotypes in mice, justifying its advance towards additional safety studies and future clinical trials. Towards developing this approach as a non-invasive treatment for Angelman syndrome, we propose to (1) establish rescue of behavioral and electrophysiological phenotypes in Angelman syndrome model mice, (2) identify the mechanism of action by which our small molecule produces unsilencing of paternal UBE3A, and (3) perform structure-activity-relationship studies to improve efficacy and maximize favorable pharmacology. By advancing the first small molecule treatment of Angelman syndrome, this research may lead to therapy yielding profound lifelong benefits for this patient population.