Transnasal Delivery of Chemokine Analogs in mouse NeuroAIDS Models

描述（由申请人提供）：近年来，HIV（人类免疫缺陷病毒）阳性个体的数量有所增加，主要是因为联合抗逆转录病毒治疗（cART）有助于这些患者活得更长。然而，艾滋病毒相关神经认知障碍（HAND）的患病率也有所上升，因为cART药物通常无法有效穿过血脑屏障。为了解决这个问题，我们建议评估一种针对HAND的新型治疗方法。在HAND患者和疾病过程的动物模型中，我们和其他人已经积累了神经元受损的证据。此外，来自我们实验室和其他实验室的新证据表明，在NeuroAids患者的大脑中，成人神经祖细胞（aNPC）也减少了。活跃的神经发生通常发生在海马齿状回的整个生命过程中。新生成的神经元被纳入神经网络，有助于某些类型的学习和记忆。有趣的是，海马神经发生显着改变，在几个神经退行性疾病除了手。最近，我们报道，HIV包膜糖蛋白gp 120，这是与手发病机制，抑制成人神经祖细胞在体外和体内的海马齿状回在NeuroAIDS啮齿动物模型，HIV/gp 120转基因小鼠的增殖。作为潜在的治疗方法，我们和我们的合作者合成了趋化因子受体（CXCR 4和CCR 5，它们是HIV/gp 120的共受体）的新肽抑制剂，并发现这些新的合成和模块化修饰（SMM）趋化因子阻断gp 120对体外神经祖细胞增殖的抑制作用。在这里，我们建议研究SMM-趋化因子在体内的有效性，从新的，非常有选择性和无毒的CXCR 4拮抗剂开始。特别是，我们建议调查是否经鼻（也称为鼻内）应用SMM-趋化因子可以防止成年神经祖细胞在NeuroAIDS小鼠模型的增殖减少。值得注意的是，我们最近已经表明，经鼻给药的肽优先递送至大脑，并且FDA已经批准其他肽以这种方式用于人类的大脑递送。本研究的具体目的如下：（1）研究经鼻注射SMM趋化因子类似物是否能保护HIV/gp 120转基因小鼠的成年神经元和恢复成年海马前体细胞的增殖。请注意，在未来的工作中，我们计划通过研究SMM-趋化因子类似物的经鼻应用是否也保护神经元并恢复第二个NeuroAIDS模型中成年海马祖细胞的增殖来测试SMM-趋化因子类似物的效果的“泛化”，该模型由NOD/scid-IL-2 Rgcnull小鼠组成，该小鼠用人造血CD 34+干细胞重建，然后感染HIV-1。该模型由我们的合作者霍华德Gendelman博士及其同事开发，虽然更难以利用，但它密切模拟了人类HAND进展和认知功能障碍。

DESCRIPTION (provided by applicant): The number of HIV (human immunodeficiency virus)-positive individuals has risen over recent years mainly because combination antiretroviral therapy (cART) is helping these patients live longer. However, the prevalence of HIV-Associated Neurocognitive Disorders (HAND) has also risen since cART drugs in general do not effectively cross the blood-brain-barrier. To address this issue, we propose to evaluate a new type of treatment targeted for HAND. In patients with HAND and in animal models of the disease process, we and others have accumulated evidence that neurons are damaged. Additionally, emerging evidence from our laboratory and others suggests that adult neuroprogenitor cells (aNPCs) are also decreased in the brains of patients with NeuroAIDs. Active neurogenesis normally occurs throughout life in the dentate gyrus in the hippocampus. Newly generated neurons are incorporated into the neural network, contributing to certain types of learning and memory. Intriguingly, hippocampal neurogenesis is significantly altered in several neurodegenerative diseases in addition to HAND. Recently, we reported that the HIV-envelope glycoprotein gp120, which is associated with HAND pathogenesis, inhibits proliferation of adult neural progenitor cells in vitro and in vivo in the dentate gyrus of the hippocampus in a NeuroAIDS rodent model, the HIV/gp120- transgenic mouse. As potential treatment, we and our collaborators have synthesized new peptide inhibitors of chemokine receptors (CXCR4 and CCR5, which are co-receptors for HIV/gp120), and found that these novel synthetically and modularly modified (SMM)-chemokines block the inhibitory effect of gp120 on neural progenitor proliferation in vitro. Here, we propose to investigate the effectiveness of SMM-chemokines in vivo, beginning with new, very selective and non-toxic CXCR4 antagonists. In particular, we propose to investigate whether transnasal (also called intranasal) application of SMM-chemokines can prevent the decrease in proliferation of adult neural progenitors in mouse models of NeuroAIDS. Notably, we have recently shown that transnasally administered-peptides are preferentially delivered to the brain, and other peptides have been approved in humans by the FDA for brain delivery in this fashion. We list the following Specific Aim: (1) To investigate whether transnasal application of SMM-chemokine analogs protects adult neurons and restores the proliferation of adult hippocampal progenitors in HIV/gp120-transgenic mice. Note that in future work, we plan to test for 'generalization' of the effect of the SMM-chemokine analogs by investigating whether transnasal application of SMM-chemokine analogs also protects neurons and restores the proliferation of adult hippocampal progenitors in a second NeuroAIDS model, consisting of NOD/scid-IL- 2Rgcnull mice that are reconstituted with human hematopoietic CD34+ stem cells and then infected with HIV-1. This model, as developed by our collaborator Dr. Howard Gendelman and colleagues, while more difficult to utilize, closely mimics human HAND progression and cognitive dysfunction.