| 项目编号: | 1743346
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| 项目名称: | Integrated Manufacturing of Therapeutic Cardiac Cells |
| 作者: | Sean Palecek
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| 承担单位: | University of Wisconsin-Madison
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| 批准年: | 2017
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| 开始日期: | 2017-09-01
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| 结束日期: | 2020-08-31
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| 资助金额: | 599447
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| 资助来源: | US-NSF
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| 项目类别: | Standard Grant
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| 国家: | US
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| 语种: | 英语
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| 特色学科分类: | Engineering - Chemical, Bioengineering, Environmental, and Transport Systems
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| 英文关键词: | manufacturing
; stem cell
; cm
; heart muscle cell
; project
; cell therapy
; epicardial cell
; epic
; cell-derived
; cell therapy manufacturing
; cost-effective manufacturing
; fetal cell
; regenerative manufacturing
; complex living cell
; cross-cellular communication
; living cell
; potent therapeutic cardiac cell
; monoculture manufacturing
; manufacturing process scale
; heart cell
; cardiac cell differentiation
; manufacturing limitation
; high quality cell
; adult cell
; scalable manufacturing platform
; cm manufacturing
|
| 英文摘要: | PI: Palecek, Sean P.
Proposal: 1743346
Cardiac disease is a leading cause of death and represents a major burden on the health care system. Patients who experience a heart attack or heart failure exhibit a permanent loss in mechanical function in their hearts, reducing quality of life and increasing the risk of later medical complications. Today there is no treatment to restore mechanical function of the heart, but the transplantation of heart muscle cells manufactured from stem cells represents a promising approach in preclinical studies and clinical trials. A current limitation of stem cell-derived heart muscle cells is they generate forces and transmit electrical currents in a manner more similar to fetal cells than adult cells. We propose to explore the notion that manufacturing heart muscle cells in conjunction with stem cell-derived epicardial cells, which provide a supportive role during heart development, will enhance the functional quality of the stem cell-derived heart cells. This project will explore whether this developmentally relevant exchange of chemical factors or direct contact between the heart muscle and epicardial cells from stem cells will improve heart muscle cell function, then use these finding to design strategies to manufacture the approximately one billion heart muscle cells necessary to replace the heart cells lost during a heart attack. This project will enable the manufacturing of sufficient quantities of high quality heart muscle cells from stem cells to facilitate preclinical and clinical studies to restore heart function in persons who have experienced heart disease. This project also addresses the lack of a trained workforce in cell therapy manufacturing. Project activities will provide unique training opportunities to undergraduates and graduate students to perform manufacturing research in partnership with industry. The project team will also develop a multi-institutional course in cell therapy manufacturing, create outreach activities related to stem cell therapies for K12 students, and refine an international short course on regenerative manufacturing targeted to graduate students and industry employees.
The next generation of therapeutics will involve living cells with the capacity to regenerate damaged or diseased human tissues. The US is poised to become a leader in cell therapies, but significant challenges in manufacturing complex living cells must be overcome. In this project we will address key roadblocks facing the cell therapy manufacturing industry including (1) lack of robust, scalable manufacturing platforms, (2) lack of knowledge of how manufacturing affects critical quality attributes (CQAs) of potency, and (3) the unavailability of a trained workforce. The project focuses on robust, scalable, and cost-effective manufacturing of safe and potent therapeutic cardiac cells from human pluripotent stem cells (hPSCs). hPSC-derived cardiomyocytes (CMs) have demonstrated improvement of ventricular contractile function in preclinical animal models. Success of impending clinical trials and development of effective human therapies will require production of high quality cells at a reasonable cost. However, scaleup of CM manufacturing reduces differentiation robustness, leading to expensive batch failures. Also, hPSC-derived CMs lack critical quality attributes (CQAs) of mature adult CMs. To address these manufacturing limitations the research team will design and evaluate a developmentally-inspired process that employs integrated manufacturing of CMs and epicardial cells (EpiCs), which provide trophic factors during heart development. This project will test the hypothesis that co-differentiation of EpiCs with CMs will generate cardiomyocytes that exhibit key maturity CQAs in a more robust, scalable manner than CMs differentiated alone. The Research Plan is organized under 3 objectives: (1) Compare robustness of integrated manufacturing of CMs and EpiCs with monoculture manufacturing as a function of differentiation scale; (2) Quantify effects of integrated manufacturing of CMs and EpiCs on acquisition of potency CQAs; and (3) Develop a scalable suspension process for integrated manufacturing of CMs and EpiCs. This project will provide a better understanding of developmentally-relevant endogenous, cross-cellular communication during integrated manufacturing of CMs and EpiCs from hPSCs. Outcomes will establish new principles for how this cross-talk affects batch-to-batch robustness of cardiac cell differentiation as the manufacturing process scales. Furthermore, this study will identify how EpiC-CM interactions during integrated manufacturing affect CQAs of both CM and EpiC products. |
| 资源类型: | 项目
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| 标识符: | http://119.78.100.158/handle/2HF3EXSE/89133
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| Appears in Collections: | 全球变化的国际研究计划
科学计划与规划
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| Recommended Citation: | |
Sean Palecek. Integrated Manufacturing of Therapeutic Cardiac Cells. 2017-01-01.
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