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

化学诱导多能干 (CiPS) 细胞 阿尔茨海默病患者特异性细胞

• 批准号: 7911334
• 负责人: Babak Esmaeli-Azad
• 金额: $ 24.72万
• 依托单位: DNAMICROARRAY, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911334
• 关键词: Adult; Alzheimer' s Disease; Autologous; Behavior; Biological Assay; Biological Models; Biopsy; Biotechnology; Cell Line; Cell Therapy; Cells; Central Nervous System Diseases; Clinical; Control Groups; DNA; Data; Degenerative Disorder; Derivation procedure; Development; Disease; Disease model; Excision; Fibroblasts; Functional disorder; Generic Drugs; Genes; Genetic Transduction; Genetic Vectors; Goals; Hand; Human; Immune; In Vitro; Inherited; Injury; Investigation; Legal patent; Libraries; Malignant - descriptor; Mediating; Medical; Methodology; Modeling; Modification; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiology; Population; Preparation; Procedures; Regenerative Medicine; Reporting; Research; Resolution; SCID Mice; Sampling; Skin; Somatic Cell; Source; Staging; Stem cells; Study models; Technology; Teratoma; Testing; Therapeutic; Tissue Engineering; Tissues; Transduction Gene; Translations; Viral; Virus; age related; base; cell bank; design; direct application; drug discovery; drug testing; embryo tissue; embryonic stem cell; expression vector; human disease; in vitro Model; induced pluripotent stem cell; mouse model; novel; novel therapeutics; phase 1 study; pluripotency; public health relevance; recombinase; small molecule; stem; tool; tool development; vector; vector-induced

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.

描述（由申请人提供）：由于缺乏真正的体外模型，研究阿尔茨海默病（AD）等人类疾病的病理生理学的努力受到阻碍。通过诱导直接重编程成体细胞产生的干细胞，称为诱导多能干细胞（iPS），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用自体细胞疗法和个性化可再生细胞来源，提供“范式转变”机会。再生医学应用，避免免疫排斥。然而，使用 iPS 细胞作为开发此类 AD 患者特异性模型系统的工具的可能性充其量仍然具有挑战性，并且由于该领域的缺点，仍然是一个明显未满足的需求。该提案中概述的研究旨在探索解决这一未满足的需求，最终目标是开发 AD 患者特异性细胞作为研究这种疾病的病理生理学和药物测试的工具。我们建议使用一种新颖、稳健、高效的 iPS 方法，该方法采用小分子诱导剂混合物，称为“化学诱导多能干细胞 (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） ）在这一阶段的研究中，这种方法的可行性将通过少量 AD 患者的皮肤活检、成纤维细胞样本的 CiPS 衍生来证明。 CiPS 患者特异性细胞的获得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性修改。拟议研究开发的工具和技术可直接应用于其他分子和细胞途径的研究。神经退行性疾病和年龄相关疾病。 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认为是了解基本疾病机制、筛选药物发现以及针对退行性疾病和严重损伤的组织工程的前所未有的机会。特别是，通过诱导直接重编程成体体细胞产生的干细胞，称为诱导多能干细胞（iPS），为研究人类疾病特异性/个性化模型提供了“范式转换”机会，并为实际的自体同源细胞提供了个性化的可再生细胞来源。避免免疫排斥的细胞疗法和再生医学应用。我们建议使用一种新颖、稳健、高效的 iPS 方法，该方法使用小分子诱导剂混合物，称为“化学诱导多能干细胞 (CiPSTM)”，无需任何外源基因转导。衍生患者特异性多能细胞，无需任何外源基因转导。对细胞和分子机制的异常和永久性修改（即迄今为止报告的所有其他 DNA 载体介导的 iPS 诱导的主要缺点） 所提议的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。