Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Brain. 2019 Feb 1;142(2):312-321. doi: 10.1093/brain/awy328.
There is increasing appreciation for the role of the neurovascular unit in neurodegenerative diseases. We showed previously that the angiogenic and neurotrophic cytokine, vascular endothelial growth factor (VEGF), is suppressed to abnormally low levels in spinocerebellar ataxia type 1 (SCA1), and that replenishing VEGF reverses the cerebellar pathology in SCA1 mice. In that study, however, we used a recombinant VEGF, which is extremely costly to manufacture and biologically unstable as well as immunogenic. To develop a more viable therapy, here we test a synthetic VEGF peptide amphiphile that self-assembles into nanoparticles. We show that this nano-VEGF has potent neurotrophic and angiogenic properties, is well-tolerated, and leads to functional improvement in SCA1 mice even when administered at advanced stages of the disease. This approach can be generalized to other neurotrophic factors or molecules that act in a paracrine manner, offering a novel therapeutic strategy for neurodegenerative conditions.
人们越来越意识到神经血管单元在神经退行性疾病中的作用。我们之前曾表明，血管生成和神经营养细胞因子血管内皮生长因子（VEGF）在脊髓小脑共济失调 1 型（SCA1）中被抑制到异常低的水平，而补充 VEGF 可逆转 SCA1 小鼠的小脑病理学。然而，在该研究中，我们使用了一种重组 VEGF，其生产成本极高，且生物稳定性和免疫原性差。为了开发更可行的治疗方法，我们在这里测试了一种可自组装成纳米颗粒的合成 VEGF 肽两亲物。我们表明，这种纳米 VEGF 具有强大的神经营养和血管生成特性，耐受性良好，甚至在疾病的晚期给药也能改善 SCA1 小鼠的功能。这种方法可以推广到其他神经营养因子或以旁分泌方式起作用的分子，为神经退行性疾病提供了一种新的治疗策略。
