Chemically Induced Pluripotent Stem (CiPS) Cells Alzheimer's Patient Specific Cel

描述（由申请人提供）：由于缺乏真正的体外模型，研究人类疾病如阿尔茨海默病（AD）的病理生理学的努力受到阻碍。通过诱导成体体细胞的直接重编程产生的干细胞（称为诱导多能干（iPS）细胞）通过提供用于研究人类疾病的特定/个性化模型以及用于实际自体细胞疗法和再生医学应用的个性化可再生细胞来源而提供“范式转变”机会，从而避免免疫排斥。然而，使用iPS细胞作为开发这种AD患者特异性模型系统的工具的可能性最多仍然具有挑战性，并且由于该领域的缺点，仍然是明显未满足的需求。本提案中概述的研究旨在探索这一未满足需求的解决方案，最终目标是开发AD患者特异性细胞，作为研究该疾病病理生理学和药物检测的工具。我们建议使用一种新的稳健和有效的iPS方法，该方法采用小分子诱导剂的混合物，称为“化学诱导的多能干细胞（CiPSTM）”，消除了对任何外源基因转导的需要（即其他人描述的iPS方法的主要障碍）。在该I期研究中，该方法的可行性将通过少量AD患者、皮肤活检、成纤维细胞样品的CiPS衍生来证明。将获得这些CiPS患者特异性细胞，而不会对通常通过其他DNA载体诱导的iPS方法观察到的细胞和分子机制进行任何异常和永久的修饰。拟议研究开发的工具和技术可直接应用于其他神经退行性疾病和年龄相关疾病的分子和细胞途径的研究。 公共卫生相关性：由于缺乏真正的体外模型，研究阿尔茨海默病等人类疾病的病理生理学的努力受到阻碍。干细胞的医学和生物技术潜力已被公认为理解基本疾病机制，筛选药物发现和组织工程退行性疾病和致残性损伤的前所未有的机会。特别地，通过诱导的成体体细胞的直接重编程产生的干细胞（称为诱导多能干（iPS）细胞）为研究人类疾病特异性/个性化模型提供了“范式转变”机会，并为避免免疫排斥的实际自体细胞疗法和再生医学应用提供了个性化的可再生细胞来源。我们建议使用一种新的强大而有效的iPS方法，该方法使用小分子诱导剂的混合物，称为“化学诱导的多能干细胞（CiPSTM）”，这消除了对任何外源基因转导的需要。衍生出患者特异性多能细胞，而对细胞和分子机制没有任何异常和永久的修饰（即，迄今报道的所有其他DNA载体介导的iPS诱导的主要缺点）。拟议研究开发的工具和技术可直接应用于其他神经退行性疾病和年龄相关疾病的分子和细胞途径的研究。

DESCRIPTION (provided by applicant): Efforts to investigate the pathophysiology of human diseases such as Alzheimer's disease (AD) are hampered by the lack of genuine in-vitro models. Stem cells generated by induced direct reprogramming of adult somatic cells, termed induced pluripotent stem (iPS) cells, offer "paradigm shifting" opportunities by providing specific/ personalized models for studying human disease, and personalized renewable source of cells for practical autologous cell therapies and regenerative medicine applications, that avoid immune rejection. The possibility of using iPS cells as a tool for development of such AD patient specific model systems, however, remains at best challenging and still a clear unmet need due to the shortcomings in this field. Studies outlined in this proposal are designed to explore resolution of this unmet need with the ultimate goal of developing AD patient specific cells as a tool for study of the pathophysiology of this disease and drug testing. We propose to use a novel robust and efficient iPS methodology which employs a cocktail of small molecule inducers, termed "Chemically induced Pluripotent Stem (CiPSTM) cells, eliminating the need for any exogenous gene transduction (i.e. a major impediment of iPS methodologies described by others). In this Phase I study, feasibility of this approach will be demonstrated via CiPS derivation of a small number of AD patients', skin biopsy, fibroblasts samples. These CiPS patient specific cells will be obtained without any abnormal and permanent modifications to the cellular and molecular machinery typically observed by other DNA vector induced iPS methodologies. Tools and technologies developed by the proposed study have direct applications to the study of molecular and cellular pathways of other neurodegenerative and age related diseases. PUBLIC HEALTH RELEVANCE: Efforts to investigate the pathophysiology of human diseases such as Alzheimer's disease are hampered by the lack of genuine in-vitro models. Medical and biotechnological potential of stem cells have been recognized as unprecedented opportunities for understanding basic disease mechanisms, screens for drug discovery, and tissue engineering for degenerative diseases and crippling injuries. In particular, stem cells generated by induced direct reprogramming of adult somatic cells, termed induced pluripotent stem (iPS) cells, offer "paradigm shifting" opportunities for studying human disease specific/ personalized models, and provide a personalized renewable source of cells for practical autologous cell therapies and regenerative medicine applications, that avoid immune rejection. We propose to use a novel robust and efficient iPS methodology that uses a cocktail of small molecule inducers, termed "Chemically induced Pluripotent Stem (CiPSTM) cells, which eliminates the need for any exogenous gene transduction. Patient specific pluripotent cells are derived, without any abnormal and permanent modifications to the cellular and molecular machinery (i.e. a major shortcoming of all other DNA vector mediated iPS inductions reported to date). Tools and technologies developed by the proposed study have direct applications to the study of molecular and cellular pathways of other neurodegenerative and age related diseases.