Developing novel treatment strategies for Spinocerebellar ataxia type 1

神经退行性疾病缺乏可行的治疗方法正成为一个日益紧迫的问题， 随着我们人口的比例越来越大，到目前为止，我们越来越容易受到这些疾病的影响 棘手的状况。挑战很多：大脑特别脆弱、复杂，而且难以接近。 我们一直在研究一种特殊的神经退行性疾病，脊髓小脑性共济失调1型(SCA1)，它 是晚发性蛋白质病家族中的一员，因此是亨廷顿病、帕金森氏症的近亲， 和肌萎缩侧索硬化症。我们意外地发现，ATXN1，一种突变的蛋白质 在SCA1中，直接调节血管生成和神经营养细胞因子VEGF的表达；此外，当 它的突变会导致SCA1小鼠大脑中血管内皮生长因子水平异常低，导致病理 神经元的微血管和树突分支的变化。我们还有 证明了这些病理以及由它们引起的运动不协调可以通过 血管内皮细胞生长因子的基因或药物补充。重组技术有严重的局限性。 然而，我们在研究中使用的血管内皮生长因子：制造成本极高，生物不稳定，而且 它具有免疫原性。出于这些原因，我们在过去的几年里一直在开发一种全新的血管内皮生长因子 试剂在我们的合作者Sam Stupp博士的帮助下，他是该领域的国际公认的专家 纳米技术和这项拨款的合作者。该试剂是一种血管内皮生长因子多肽两亲性(VEGF-PA)，即 免疫原性较低，旨在水环境中自组装成稳定的多肽两亲性 纳米粒子。我们的初步数据表明，VEGF-PA对SCA1小鼠是有效的。在本提案中，我们将 血管内皮生长因子-PA纳米肽作为生化稳定、廉价替代物的可行性研究 将重组血管内皮生长因子用于小脑变性的长期治疗。我们希望我们的学习能取得进步 这项纳米技术将用于治疗SCA1的临床试验。鉴于缺乏血管内皮生长因子被认为与 在包括运动神经元障碍和帕金森病在内的广泛的神经退行性疾病中，我们的 在SCA1上的工作有可能彻底改变神经退行性变的治疗方法。此外，这些研究将 为基于纳米药物的治疗方法用于取代其他神经营养因子铺平道路，具有广泛的 对许多疾病的潜在治疗方法的影响。

The lack of viable treatments for neurodegenerative diseases is becoming an increasingly pressing problem, as an ever-larger proportion of our population advances in years and becomes susceptible to these so far intractable conditions. The challenges are many: the brain is particularly delicate, complex, and inaccessible. We have been studying a particular neurodegenerative disease, Spinocerebellar ataxia type 1 (SCA1), which is one of a family of late-onset proteinopathies and thus a close cousin to Huntington's disease, Parkinson's, and amyotrophic lateral sclerosis. We made the unexpected discovery that ATXN1, the protein that is mutated in SCA1, directly regulates the expression of the angiogenic and neurotrophic cytokine VEGF; moreover, when mutated it causes the levels of VEGF to be abnormally low in the SCA1 mouse brain, causing pathological changes in the microvasculature as well as in the dendritic arborization of neurons. We have also demonstrated that these pathologies, and the motor incoordination that results from them, can be reversed by either genetic or pharmacologic replenishment of VEGF. There are severe limitations to the recombinant VEGF we had used in our study, however: it is extremely costly to manufacture, it is biologically unstable, and it is immunogenic. For these reasons, we have spent the past few years developing a completely new VEGF reagent with the help of our collaborator Dr. Sam Stupp, an internationally recognized expert in the field of nanotechnology and a collaborator on this grant. The reagent is a VEGF peptide amphiphile (VEGF-PA) that is less immunogenic and is designed to self-assemble in an aqueous environment into stable peptide amphiphile nanoparticles. Our preliminary data indicate that VEGF-PA is effective in SCA1 mice. In this proposal we will establish the feasibility of using VEGF-PA nano-peptide as a biochemically stable and inexpensive alternative to recombinant VEGF for long-term therapy for cerebellar degeneration. We hope that our studies will advance this nanotechnology toward clinical trials for treating SCA1. Given that deficiency in VEGF has been implicated in a wide range of neurodegenerative diseases including motor neuron disorders and Parkinson's disease, our work in SCA1 has the potential to revolutionize treatment for neurodegeneration. Moreover, these studies will pave the way for nanomedicine based treatments to be used to replace other neurotrophic factors, with broad ramifications for potential therapies for many diseases.