Microfluidic cell squeezing platform for the transdifferentiation of somatic cells for efficient generation of a cell replacement therapy for Parkinsons Disease

用于体细胞转分化的微流控细胞挤压平台，可有效生成帕金森病的细胞替代疗法

• 批准号: 10483308
• 负责人: Devin Bridgen
• 金额: $ 100.14万
• 依托单位: SQZ BIOTECHNOLOGIES COMPANY, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-14 至 2022-12-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483308
• 关键词: Affect; Age related macular degeneration; Allogenic; Animal Model; Autologous; Biopsy; Blood Cells; Cell Differentiation process; Cell Therapy; Cell Transplantation; Cells; Chronic; Clinic; Clinical; DNA Sequence Alteration; Data; Degenerative Disorder; Development; Disease; Disease model; Dose; Electrophysiology (science); Electroporation; Engineering; Engraftment; Ensure; Failure; Gene Expression; Generations; Genetic; Genetic Risk; Goals; Health; Heart failure; Human; Human Engineering; Immune; Immunosuppression; In Vitro; Insulin-Dependent Diabetes Mellitus; Legal patent; Liver Failure; Macular degeneration; Mammalian Cell; Messenger RNA; Methods; Microfluidics; Modeling; Modification; Molecular; Morphology; Mus; Nerve Degeneration; Neurons; Nucleic Acids; Organ; Oxidopamine; Parkinson Disease; Patient-Focused Outcomes; Patients; Peptides; Peripheral Blood Mononuclear Cell; Pharmacologic Substance; Phase; Physiological; Play; Pluripotent Stem Cells; Population; Pre-Clinical Model; Process; Production; Proteins; Quality of life; Rattus; Research; Risk; Safety; Signal Pathway; Small Business Innovation Research Grant; Solid Neoplasm; Somatic Cell; Symptoms; System; Technology; Therapeutic; Thromboplastin; Time; Tissues; Translating; Transplantation; Viral Vector; Work; age related; base; biopharmaceutical industry; cell injury; cell replacement therapy; cell transformation; cell type; clinical translation; clinically relevant; dopaminergic neuron; improved; in vivo; in vivo engraftment; induced pluripotent stem cell; lipofection; macula; neurotransmission; phase I trial; prevent; programs; reduce symptoms; stem cells; transcription factor; transdifferentiation; viral gene delivery; virtual delivery

PROJECT SUMMARY: Major diseases, such as heart failure, Parkinson’s Disease (PD), type 1 diabetes, and age-related macular de- generation, are examples of organ and systemic failure driven by damage to specific cell types. One possible therapeutic solution is to replace the damaged cells with ex vivo engineered, physiologically functional cells to alleviate clinical symptoms. However, expensive, time-intensive, and inefficient cell reprogramming methods for generating transplantable therapeutic cells for degenerative disorders hinders development and clinical transla- tion of potentially transformative therapies. Our goal is to develop a highly efficient process for producing cell replacement therapies that can be reliably manufactured at-scale to treat currently intractable diseases such as Parkinson’s Disease. This goal will build upon our patented and proven Cell Squeeze® technology that can deliver materials including mRNA, proteins, and peptides into sensitive primary cells. For this Phase II SBIR proposal, our overall objective is to demonstrate that with Cell Squeeze® technology we can introduce transcrip- tion factors that can increase the efficiency of transdifferentiating peripheral blood cells (PBMCs) into clinically relevant dopaminergic neurons. Our central hypothesis is that we can precisely control the timing, dose, and combinations of transcription factors to create high quality, functional cell products in greater quantities in a shorter time than is possible with current methods and free of risks associated with viral gene delivery. Support- ing this goal, we have already demonstrated that the squeeze treatment alone does not significantly affect gene expression, we can efficiently generate neurons from iPSCs, and we can introduce multiple transcription factors into PBMCs to upregulate expression of key neuronal signaling pathways. The rationale is that our non-viral method of delivering transcription factors to drive cell fate could significantly improve the efficiency and efficacy of cells produced with fewer safety and regulatory concerns as compared to other methods of transdifferentiation. Furthermore, in comparison to allogeneic iPSC derived products, autologous cells would not require chronic immunosuppression – a key factor to ensure long term health of the patient. In Aim 1, we seek to optimize methods for the Cell Squeeze® technology to deliver mRNA-based transcription factors to PBMCs to drive effi- cient transdifferentiation into dopaminergic neurons (DNs). Resultant DNs will be thoroughly characterized in vitro and compared to DN generated from iPSC using existing methods. In Aim 2, these DNs will be functionally assessed in an in vivo murine PD model to support the further development into a potentially transformative cell therapy. Successful completion of these aims may support partnering opportunities with other biopharmaceutical companies who are seeking differentiated cell therapy approaches in neurodegeneration.

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