STTR Phase I: Autologous Hematopoietic Stem Cell Production to End Graft-Versus-Host Disease

STTR 第一阶段：自体造血干细胞生产以终结移植物抗宿主病

• 批准号: 2035827
• 负责人: Christian Macedonia
• 金额: $ 25.6万
• 依托单位: IREPROGRAM, LLC
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2035827&HistoricalAwards=false
• 关键词: STTR; Phase; Autologous; Hematopoietic; Stem

The broader impact of this Small Business Technology Transfer (STTR) Phase I project is the potential elimination of Graft-Versus-Host Disease (GVHD). GVHD is a devastating illness that afflicts transplant recipients who are recovering from chemotherapy and who suffer from suppression of their bone marrow function and immune system. GVHD associated illnesses lead to a very high rate of premature death in these patients. This project focuses on the development of a novel biocomputational platform to generate patient-derived stem cells to be subsequently reintroduced to the same cancer patient. This completely bypasses third-party bone marrow and blood donations, decreasing, and potentially eliminating, lethal GVHD and drastically improving outcomes. The use of cells derived directly from the same patient (e.g. skin cells) to reconstitute the blood system is considered one of the highest and most challenging goals of blood system regenerative biology research. This will advance bioinformatics and cell therapy research and will advance the state-of-the-art in cancer treatment and personalized medicine.The proposed project will use a high-fidelity prototype computational tool to generate transcription factor recipes for cellular transdifferentiation, test those predicted recipes through systematic and high-throughput wetlab validations, and demonstrate proof of concept for the autologous production of persistent HSCs that maintain long-term multilineage engraftment and self-renewal, potentially enabling recapitulation of the entire blood lineage. The project scope includes an effort to survey, identify, and procure appropriate initial cell types; determine cell type-specific predictions for reprogramming into HSCs; prioritize the most promising recipes and carry out appropriate viral transductions; create an in vitro analog of target HSCs and determine alignment with the human HSC phenotype; and perform reprogramming experiments for the top transcription factor recipes. Data analysis will include key comparisons of reprogrammed HSCs, in vitro analog HSCs, primary human HSCs, and data from prior published efforts to produce HSCs. HSCs are fundamentally different from the differentiated cell types previously targeted with the computational tool, as they retain proliferative potential and are therefore very difficult to generate. Proof of concept in this challenging system will not only address GVHD, but also further prove the efficacy of the overall biocomputational platform for use in numerous other biological systems and potential cures.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该小企业技术转让 (STTR) 第一阶段项目的更广泛影响是有可能消除移植物抗宿主病 (GVHD)。 GVHD 是一种毁灭性的疾病，困扰着正在从化疗中恢复的移植受者，他们的骨髓功能和免疫系统受到抑制。 GVHD 相关疾病导致这些患者过早死亡的比例非常高。该项目的重点是开发一种新型生物计算平台，以生成源自患者的干细胞，然后将其重新引入同一癌症患者体内。这完全绕过了第三方骨髓和献血，减少并有可能消除致命的 GVHD，并显着改善结果。使用直接源自同一患者的细胞（例如皮肤细胞）来重建血液系统被认为是血液系统再生生物学研究的最高和最具挑战性的目标之一。这将推进生物信息学和细胞治疗研究，并将推进癌症治疗和个性化医疗的最先进水平。拟议项目将使用高保真原型计算工具来生成用于细胞转分化的转录因子配方，通过系统和高通量湿实验室验证测试这些预测的配方，并展示自体生产维持长期多谱系的持久性 HSC 的概念证明 植入和自我更新，有可能实现整个血统的重现。项目范围包括调查、识别和采购适当的初始细胞类型；确定重编程为 HSC 的细胞类型特异性预测；优先考虑最有希望的配方并进行适当的病毒转导；创建目标 HSC 的体外类似物并确定与人类 HSC 表型的一致性；并对顶级转录因子配方进行重编程实验。数据分析将包括重编程 HSC、体外模拟 HSC、原代人类 HSC 以及之前发表的 HSC 生产数据的关键比较。 HSC 与之前使用计算工具靶向的分化细胞类型有根本的不同，因为它们保留了增殖潜力，因此很难生成。这一具有挑战性的系统中的概念验证不仅将解决 GVHD 问题，还将进一步证明整个生物计算平台在许多其他生物系统和潜在治疗中使用的有效性。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。