Developing novel treatment strategies for Spinocerebellar ataxia type 1

开发 1 型脊髓小脑共济失调的新治疗策略

• 批准号: 9226821
• 负责人: Puneet Opal
• 金额: $ 23.53万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226821
• 关键词: Abnormal coordination; Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Angiogenic Factor; Area; Ataxia; Attention; Behavioral; Biochemical; Biocompatible Materials; Biological; Brain; Brain Stem; CAG repeat; Cerebellar degeneration; Cessation of life; Clinic; Clinical Trials; Complex; Data; Disease; Disease Progression; Environment; Face; Family; Functional disorder; Genes; Genetic; Genetic Transcription; Glutamine; Goals; Grant; Growth Factor; Hippocampus (Brain); Huntington Disease; Inherited; International; Knock-in Mouse; Modeling; Motor; Motor Neurons; Mus; Mutate; Names; Nanotechnology; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Paralysed; Parkinson Disease; Pathologic; Pathology; Patients; Peptides; Pharmacology; Phenotype; Physiological; Play; Population; Preclinical Testing; Property; Proteins; Purkinje Cells; Reagent; Recombinant Vascular Endothelial Growth Factor; Recombinants; Research; Role; Signal Transduction; Spinocerebellar Ataxias; Symptoms; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxic effect; Treatment Protocols; Type 1 Spinocerebellar Ataxia; VEGFA gene; Vascular Endothelial Growth Factors; Work; aging population; aqueous; ataxin-1; base; cost; cytokine; design; dosage; human disease; imaging biomarker; immunogenic; innovation; middle age; misfolded protein; mutant; nano; nanomedicine; nanoparticle; neurotrophic factor; novel; novel therapeutics; outcome forecast; overexpression; peptidomimetics; polyglutamine; reduce symptoms; spinal and bulbar muscular atrophy; treatment strategy

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.

缺乏针对神经退行性疾病的可行治疗正在成为一个越来越紧迫的问题， 随着多年来我们人口的不断增长，到目前为止都容易受到这些影响 棘手的条件。挑战很多：大脑特别精致，复杂且无法访问。 我们一直在研究一种特定的神经退行性疾病，脊髓脑性共济失调1型（SCA1），该疾病 是一个晚期蛋白质病的家族之一，因此是亨廷顿氏病，帕金森氏病的堂兄， 和肌萎缩性侧硬化症。我们意外发现的是，Atxn1是突变的蛋白质 在SCA1中，直接调节血管生成和神经营养性细胞因子VEGF的表达；而且，什么时候 突变导致SCA1小鼠大脑中VEGF的水平异常低，导致病理 微脉管系统的变化以及神经元的树突状树皮化的变化。我们也有 证明这些病理以及从中导致的运动不协调可以逆转 VEGF的遗传或药理补充。重组有严重的限制 但是，我们在研究中使用的VEGF：生产的成本非常高，它在生物学上不稳定，并且 它是免疫原性的。由于这些原因，我们过去几年来开发了一个全新的VEGF 试剂在我们的合作者Sam Stupp博士的帮助下，该领域是国际认可的专家 纳米技术和该赠款的合作者。该试剂是VEGF肽两亲物（VEGF-PA），即 较少的免疫原性，设计为在水性环境中自组装成稳定的肽 纳米颗粒。我们的初步数据表明VEGF-PA在SCA1小鼠中有效。在这个建议中，我们将 建立使用VEGF-PA纳米肽作为生化稳定且廉价的替代方案的可行性 重组VEGF用于长期治疗小脑变性。我们希望我们的学习能够进步 该纳米技术用于治疗SCA1的临床试验。鉴于VEGF缺乏涉及 在各种神经退行性疾病中，包括运动神经元疾病和帕金森氏病，我们 SCA1中的工作有可能彻底改变神经退行性的治疗。而且，这些研究将 为基于纳米医学的治疗铺平道路，用于替代其他神经营养因素， 对许多疾病的潜在疗法的影响。