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，

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.