Small Molecule Therapeutic Discovery for Angelman Syndrome

项目摘要 Angelman综合征是一种严重的神经发育障碍，由UBE3A的母体等位基因缺失引起。 在神经元中，UBE3A的父系等位基因在表观遗传学上是沉默的。解除UBE3A父系等位基因的沉默 为治疗安格尔曼综合征提供了一个潜在的变革机会。我们最近发现了一个小的 在Angelman综合征模型培养的神经元中使UBE 3A的父系等位基因不沉默的分子 小鼠或源自Angelman综合征个体的干细胞。当非侵入性地输送到 Angelman综合征模型小鼠，这种小分子导致全脑神经元UBE 3A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Angelman 在小鼠中的综合征表型，证明其对额外的安全性研究和未来的临床试验的进展。 为了发展这种方法作为一种非侵入性治疗Angelman综合征，我们建议（1） 在Angelman综合征模型小鼠中建立行为和电生理表型拯救，（2） 确定我们的小分子产生父本UBE 3A非沉默的作用机制，以及（3） 进行构效关系研究，以提高疗效并最大限度地发挥有利的药理作用。通过 这项研究推进了Angelman综合征的第一个小分子治疗， 对这一患者群体有着深远的终身益处。

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.