HIV/NeuroAIDS Patient Derived Induced Pluripotent Stem (iPS) Cells

描述（由申请人提供）：这是一份SBIR I期申请，用于资助从滥用酒精和/或其他物质（如可卡因、鸦片等）的HIV/神经艾滋病患者群体中开发诱导多能干细胞（iPS）的概念证明研究。人们普遍认为，酒精和滥用药物是人类免疫缺陷病毒（HIV）诱发疾病进展的重要辅助因素。HIV感染、酒精和药物滥用会严重影响免疫系统和中枢神经系统。在艾滋病毒患者中，异常交叉导致一系列被称为神经艾滋病的症状。“神经艾滋病”一词包括无数种新型神经系统疾病，这些疾病是HIV对中枢和周围神经系统造成损害的主要后果。医疗条件包括感觉神经病变、脊髓病、HIV痴呆和认知/运动障碍异常。在少数群体中，艾滋病毒感染和神经艾滋病的进展率不成比例。在一个种族群体中存在的生物差异可能会加剧向神经艾滋病的转化率，这是未知的。为了了解酒精和药物滥用对神经艾滋病的潜在机制，必须进行更明确的研究，特别是检查神经免疫、潜在中枢神经系统储库、神经元和神经胶质细胞。我们建议从从酗酒和/或吸毒的少数HIV患者身上收集的成纤维细胞样本中制造iPS细胞。与人类胚胎干细胞（hESCs）一样，iPS细胞可以无限自我更新，并可以分化为人体的大多数细胞，包括中枢神经系统。此外，iPS细胞既可以通过靶向基因破坏进行修饰，也可以作为疾病特异性细胞系从患者身上制造出来。我们已经成功地将iPS细胞和hESCs分化成神经元谱系，以研究各种药物和已知毒素（如酒精）对神经退行性的影响。我们已经成功地确定了在神经发生过程中受酒精差异调节的基因。我们相信iPS细胞是一个强大的工具，可以深入了解哪些生物标志物对滥用药物感染艾滋病毒的人群发展为神经艾滋病至关重要。从病人的大脑中获取原代细胞只会加剧他们目前的神经问题。这项提议的成功将创造出第一个用于观察神经艾滋病生物标志物的细胞系。已发表的关于进入人体临床试验的药物的报告估计，根据治疗方法的不同，成本从5亿美元到20亿美元不等。所有进入I期试验的新药和成功完成人体使用产品许可的成功率约为9%，同时，中枢神经系统候选药物上市治疗的成功率预计为3%。几种药物已经在艾滋病毒相关痴呆（HAD）的I期和II期临床试验中进行了测试，这通常与艾滋病毒/神经艾滋病有关，不幸的是，没有一项研究能够改善健康状况。显然有必要提高生产力并降低药物开发成本，使用既鼓励创新又确保药物安全性和有效性的战略。HIV/神经艾滋病患者来源的iPS细胞是研究中枢神经系统发育的一个模型；功能和疾病是补充体内实验的有用工具。我们建议，目前与药物开发相关的低效率、高损耗率、长时间的研发周期和高成本可以通过HIV/神经艾滋病患者来源的iPS细胞的出现而减少，这种细胞相对便宜，可以作为生物技术和制药行业中第一阶段药物发现和临床前产品开发的高通量体外分析模型。这个I期申请的具体目标是：具体目标#1：从药物滥用少数群体和非少数群体HIV/神经艾滋病患者的成纤维细胞中制造iPS细胞。特异性目标#2：将iPS细胞分化为神经元和胶质细胞谱系。这项工作的成功完成将支持二期申请，目标是包括更大的iPS细胞开发队列，毒理学筛选和产品获得FDA 510(k)批准。

DESCRIPTION (provided by applicant): This is an SBIR Phase I re-submission to fund proof of concept studies for the development of induced pluripotent stem (iPS) cells from a population of HIV/NeuroAIDS patients who abuse alcohol and/or other substances (i.e. cocaine, opium, etc). It has been accepted that alcohol and drugs of abuse are significant cofactors in the progression of human immunodeficiency virus (HIV)-induced disease. HIV infection, alcohol and drugs of abuse significantly affect the immune system as well as the central nervous system (CNS). In patients with HIV, abnormalities intersect to lead to a constellation of symptoms known as NeuroAIDS. The term "NeuroAIDS" includes a myriad of novel neurologic disorders which are a primary consequence of damage to the central and peripheral nervous system by HIV. The medical conditions include sensory neuropathy, myelopathy, HIV dementia, and cognitive/motor disorder abnormalities. In minority groups HIV infection and NeuroAIDS progression occur at a disproportionate rate. The existence of biological differences within an ethnic group which might exacerbate the rate of conversion to NeuroAIDS is unknown. More definitive research has to be performed to understand the underlying mechanisms of alcohol and drug abuse on NeuroAIDS, specifically examining neuroimmunity, latent CNS reservoirs, neurons and glial cells. We are proposing to create iPS cell from fibroblast samples collected from minority HIV patients who abuse alcohol and/or drugs. Like human embryonic stem cells (hESCs), iPS cells can self-renew indefinitely and can be differentiated into most cells of the human body, including the CNS. Furthermore, iPS cells can either be modified by targeted gene disruption or created from patients as disease specific cell lines. We have successfully differentiated iPS cells and hESCs into neuronal lineages to study the neurodegenerative effect of various drugs and known toxins such as alcohol. We have successfully identified genes that are differentially regulated by alcohol during neurogenesis. We believe iPS cells to be a powerful tool in gaining insight into which biomarkers are essential for the progression to NeuroAIDS in populations infected with HIV while abusing substances. Obtaining primary cells from a patient's brain would only exacerbate their current neurological problem. The success of this proposal will create the first cell line that is designed to look at biomarkers of NeuroAIDS. Published reports for drugs entering human clinical trials estimate costs to vary from $500 million to $2 billion depending on the therapy. The success rate for all new drugs entering phase I trials and the successful completion of product licensing for human use is approximately 9%, meanwhile, the success rate for CNS drug candidates to become marketed therapeutic is projected at 3%. Several drugs have been tested in phase I and II clinical trials for HIV-associated dementia (HAD), which is commonly associated with HIV/NeuroAIDS and unfortunately none of the studies were able to improve health conditions. There is clearly a need to increase productivity and decrease the cost of drug development using strategies that also encourage innovation while ensuring drug safety and efficacy. HIV/NeuroAIDS patient-derived iPS cells represent a model to study CNS development; function and disease and are a useful tool to complement in vivo experimentation. We propose that the current inefficiencies, high attrition rates, protracted R&D cycles and elevated cost associated with drug development can be reduced by the advent of HIV/NeuroAIDS patient derived iPS cells which are relatively inexpensive and can be used as a model for high- throughput in vitro analysis in first phase drug discovery and preclinical product development in the biotechnology and pharmaceutical industry. The Specific Aims of this Phase I application are: Specific Aim #1: To create iPS cells from fibroblast cells taken from substance abusing minorities and non-minorities with HIV/NeuroAIDS. Specific Aim #2: Differentiate iPS cells into neuronal and glial cell lineages. Successful completion of this work will support a Phase II application, with the goals of including a larger cohort for iPS cell development, toxicology screening and the product leading to FDA 510(k) approval. PUBLIC HEALTH RELEVANCE: There is clearly a need to increase productivity and decrease the cost of drug development to treat HIV/NeuroAIDS using strategies that also encourage innovation while ensuring drug safety and efficacy. We propose that the current inefficiencies, high attrition rates, protracted R&D cycles and elevated cost associated with drug development can be reduced by the advent of HIV/NeuroAIDS patient derived iPS cells which are relatively inexpensive and can be used as a model for high-throughput in vitro analysis in first phase drug discovery and preclinical product development in the biotechnology and pharmaceutical industry.