VEGF-Mimetic Supramolecular Nanoparticles for Treating Spinocerebellar Ataxia Type 1

脊髓小脑性共济失调1型(SCA1)是一种进行性神经退行性疾病，由 多聚谷氨酰胺在ATXN1蛋白中的扩张。在描述早期机制的过程中 在神经变性的基础上，我们有了一个意想不到的发现，即ATXN1直接调节 血管生成和神经营养细胞因子血管内皮生长因子的表达及其水平异常 在SCA1小鼠大脑中含量较低，会造成病理后果。自那以后，我们发现交付 重组血管内皮生长因子对具有良好特征的SCA1基因敲除小鼠具有治疗作用(SCA1154Q/2Q； Q=谷氨酰胺)，这是现存最精确的SCA1小鼠模型。然而，也有几个挑战 以开发重组血管内皮生长因子作为治疗方法。在这里，我们建议在最近工作的基础上再接再厉 开发一种易于合成的类似血管内皮生长因子的颗粒，具有更大的潜力 在神经元和内皮细胞上激活血管内皮生长因子受体以维持神经血管健康 SCA1。其目标是为SCA1设计一种一流的纳米疗法。

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a polyglutamine expansion in the protein ATXN1. In the course of delineating early mechanisms underlying neurodegeneration, we made the unexpected discovery that ATXN1 directly regulates the expression of the angiogenic and neurotrophic cytokine VEGF and that VEGF levels are abnormally low in the SCA1 mouse brain with pathologic consequences. We have since discovered that delivering recombinant VEGF is therapeutic in the well-characterized SCA1 knock-in mouse (SCA1154Q/2Q; Q=glutamine), the most precise existing mouse model of SCA1. However, there are several challenges with developing recombinant VEGF as a therapy. Here we propose to build upon our recent work developing a VEGF-mimetic particle that could be readily synthesized with a greater potential to engage VEGF receptors in both neurons and endothelial cells to maintain neurovascular health in SCA1. The goal is to engineer a first-in-class nanotherapy for SCA1.