Transnasal Delivery of Chemokine Analogs in mouse NeuroAIDS Models

描述(由申请人提供)：HIV(人类免疫缺陷病毒)阳性患者的数量近年来有所上升，主要是因为联合抗逆转录病毒疗法(CART)正在帮助这些患者延长寿命。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药物通常不能有效地通过血脑屏障。为了解决这个问题，我们建议评估一种针对手部的新型治疗方法。在手部的患者和疾病过程的动物模型中，我们和其他人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，神经艾滋病患者的大脑中成人神经前体细胞(ANPC)也减少。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。新产生的神经元被整合到神经网络中，有助于某些类型的学习和记忆。有趣的是，除了手部，海马区的神经发生在几种神经退行性疾病中也发生了显著改变。最近，我们报道了与手部发病相关的HIV包膜糖蛋白gp120在体外和体内抑制成年神经前体细胞在神经艾滋病啮齿动物模型-HIV/gp120转基因小鼠的海马齿状回的增殖。作为潜在的治疗方法，我们和我们的合作者已经合成了新的趋化因子受体的多肽抑制剂(HIV/gp120的共同受体CXCR4和CCR5)，并发现这些新的合成和模块修饰的(SMM)趋化因子在体外可以阻断gp120对神经前体细胞增殖的抑制作用。在这里，我们建议从新的、非常选择性和无毒的CXCR4拮抗剂开始，研究SMM趋化因子在体内的有效性。特别是，我们建议通过鼻腔(也称为鼻内)应用SMM-趋化因子是否可以阻止神经艾滋病小鼠模型中成年神经前体细胞增殖的减少。值得注意的是，我们最近表明，经鼻给药的多肽优先被输送到大脑，FDA已经批准其他多肽以这种方式在人类体内输送。我们列出了以下具体目的：(1)研究鼻腔应用SMM-趋化因子类似物是否保护成年神经元并恢复成年海马祖细胞在HIV/gp120转基因小鼠中的增殖。请注意，在未来的工作中，我们计划通过研究经鼻应用SMM-趋化因子类似物是否也保护神经元并恢复第二个神经艾滋病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“泛化”效果，该模型由NOD/SCID-IL-2Rgcull小鼠组成，这些小鼠与人造血CD34干细胞重组，然后感染HIV-1。这个模型是由我们的合作者Howard Gendelman博士和他的同事开发的，虽然使用起来比较困难，但它非常接近地模拟了人类的手的进程和认知功能障碍。

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.