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， 随着年龄的增长，我们人口中越来越大的比例变得容易受到这些因素的影响 棘手的情况。挑战很多：大脑特别脆弱，复杂，难以接近。 我们一直在研究一种特殊的神经退行性疾病，脊髓小脑共济失调1型（SCA 1）， 是晚发性蛋白质病家族中的一员，因此是亨廷顿病、帕金森病 和肌萎缩侧索硬化症。我们意外地发现ATXN 1，突变的蛋白质 在SCA 1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 突变导致SCA 1小鼠脑中VEGF水平异常低，导致病理性 微血管系统的变化以及神经元的树突状分支。我们还 证明了这些病理，以及由它们引起的运动不协调，可以通过 VEGF的遗传或药理学补充。重组体存在严重的局限性， 然而，我们在研究中使用的VEGF：制造成本极高，生物学不稳定， 它具有免疫原性。由于这些原因，我们在过去的几年里开发了一种全新的VEGF， 在我们的合作者Sam Stupp博士的帮助下，该试剂是国际公认的试剂领域的专家。 纳米技术和一个合作者。该试剂是VEGF肽两亲物（VEGF-PA）， 免疫原性较低且被设计成在水性环境中自组装成稳定肽两亲物 纳米粒子我们的初步数据表明VEGF-PA在SCA 1小鼠中是有效的。在本提案中，我们将 建立使用VEGF-PA纳米肽作为生物化学稳定和廉价替代品的可行性 重组VEGF长期治疗小脑变性。我们希望我们的研究能有所进展 将这项纳米技术用于治疗SCA 1的临床试验。鉴于VEGF的缺乏与 在广泛的神经退行性疾病，包括运动神经元疾病和帕金森病，我们的 SCA 1的工作有可能彻底改变神经变性的治疗。此外，这些研究将 为纳米医学为基础的治疗铺平了道路，用于取代其他神经营养因子，广泛 对许多疾病的潜在疗法的影响。

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.