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。通过诱导成年体细胞直接重编程产生的干细胞，称为诱导多能干细胞，通过为研究人类疾病提供特定/个性化模型，以及为实际的自体细胞治疗和再生医学应用提供个性化可再生细胞来源，从而提供“范式转换”机会，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，由于该领域的缺点，充其量仍然具有挑战性，并且仍然是一个明显未满足的需求。本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，作为研究该疾病病理生理学和药物测试的工具。我们建议使用一种新的强大而有效的iPS方法，该方法采用一种称为“化学诱导多能干细胞（CiPSTM）”的小分子诱导剂混合物，消除了对任何外源基因转导的需要（即其他iPS方法的主要障碍）。在这项I期研究中，将通过少量AD患者皮肤活检、成纤维细胞样本的CiPS衍生来证明该方法的可行性。这些CiPS患者特异性细胞将不会对其他DNA载体诱导iPS方法通常观察到的细胞和分子机制产生任何异常和永久性的改变。该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。