Samaritan Compounds Suppress Viral Replication and Prevent Neuronal Damage

描述（由申请人提供）：目前，高达50%的艾滋病毒感染者（包括接受抗逆转录病毒治疗的人）患有轻度神经认知障碍。此外，感染艾滋病毒的人口继续增长，现在美国有超过100万人感染艾滋病毒，全世界有4200万人。这表明持续的HIV相关认知障碍是全球神经认知障碍的最常见原因。虽然随着抗逆转录病毒药物的出现，在治疗和前景方面取得了重大进展，但HNCI仍然是艾滋病毒感染者的一个重大负担，迄今没有具体的治疗方法。HNCI已被证明发生在感染的无症状阶段，随着疾病的进展而增加其患病率7，并且尽管HAART成功进行免疫重建，但仍持续存在。即使是轻微的HNCIs也会对日常功能产生重大影响。与认知功能完好的艾滋病毒感染者相比，受损者的生活质量较低，更有可能失业8 9，在药物管理10、11以及其他日常生活活动11方面有困难。HNCI的影响因辅助因素而进一步复杂化，如药物滥用和与丙型肝炎合并感染，这两者都被认为是加剧认知障碍12，13。这些附加的不良反应强调了各种症状和治疗结果之间关系的重要性，这可以转化为HNCI和预期寿命之间的关系。这项研究的科学意义在于，它将在缺乏这种治疗的情况下，以及当目前的抗逆转录病毒治疗在大脑中不完全有效时，确定针对艾滋病毒的脑靶向治疗。因此，鉴定具有可证实的抑制脑病毒复制和最小化HIV相关神经变性的能力的新型抗病毒药物将有助于临床医生定制药物方案以包括此类药物以预防或治疗HNCI。总之，这个为期12个月的第一阶段项目将在人类大脑模型中生成撒玛利亚分子抑制病毒复制和预防HIV相关神经变性的能力的数据，这两种病理事件是HNCI的基础。该项目的数据将成为STTR II期试验的基础，该试验将在体外人脑聚集体模型中将撒玛利亚分子的测试扩展到其他病毒株，在SIV感染的灵长类动物中进行评估，并进一步进行临床前研究，这些研究是在HNCI患者中进行临床试验所需的。 这些研究将使我们能够测试撒玛利亚分子抑制病毒复制的能力，并通过利用我们感染艾滋病毒的人脑聚集体模型来防止神经退行性变。目前，只有少量的数据确定哪些抗逆转录病毒药物在抑制病毒复制或预防神经退行性变方面最成功，尽管对该疗法的需求不断增长。如果这些研究和相关的开发计划证明是成功的，撒玛利亚分子将被进一步开发为有前途的HIV神经变性治疗剂。

DESCRIPTION (provided by applicant): Currently up to 50% of HIV infected individuals including those taking antiretroviral therapy have mild neurocognitive disorder. Furthermore, the population living with HIV infection continues to grow and there are now over one million people living with HIV in the US and 42 million around the world. This indicates that persistent HIV associated cognitive impairment is the most common cause of neurocognitive disorder globally. While significant progress has been made in the treatment and outlook with the advent of antiretroviral medication, HNCI remains a significant burden to persons living with HIV infection and to date has no specific therapy. HNCI has been shown to occur during asymptomatic stages of infection, to increase its prevalence as the illness progresses 7 and to persist despite successful immune reconstitution with HAART. Even mild HNCIs have a significant impact on daily functioning. Compared to cognitively intact HIV infected individuals, impaired persons have a lower quality of life , are more likely to be unemployed 8 9 and have difficulty with medication management 10,11 as well as other activities of daily living 11. The impact of HNCI is further complicated by co-factors such as substance misuse and co-infection with hepatitis C, both of which are being recognized as exacerbating cognitive impairment 12,13 . These additive adverse effects emphasize the importance of the relationship between various symptoms experienced and treatment outcomes, which could be translated as the relationship between HNCI and life expectancy. The scientific significance of this investigation is it will identify brain targeted therapy for HIV in the absence of such therapy and when current antiretroviral therapy is not completely effective in the brain. Thus, identification of novel antiviral drugs that have demonstrable ability to suppress brain viral replication and minimize HIV associated neurodegeneration will assist clinicians in tailoring drug regimes to include such agents in order to prevent or treat HNCI. In summary this 12 month phase I project will generate data in a human brain model of the ability of Samaritan molecules to suppress viral replication and prevent HIV associated neurodegeneration, two pathological events that underlie HNCI. The data from this project will then be the foundation for an STTR phase II trial which will expand the testing of the Samaritan molecules to other viral strains in the in vitro human brain aggregate model, evaluation in SIV infected primates and further preclinical studies that are required to proceed with clinical trials in individuals with HNCI. These studies will allow us to test the ability of the Samaritan molecules to suppress viral replication and prevent neurodegeneration by exploiting our human brain aggregate model infected with HIV. At present, only a modest amount of data identifies which antiretroviral agents are the most successful at suppressing viral replication or preventing neurodegeneration despite a growing need for the therapy. Should these studies and the associated development plans prove successful, the Samaritan molecules will be further developed as promising HIV neurodegeneration therapeutics.