HEXAGEN Harnessing haematopoietic stem cell EX vivo Adaptation for GENe therapy

HEXAGEN 利用造血干细胞离体适应 GENe 疗法

• 批准号: EP/Y026586/1
• 负责人: Elisa Laurenti
• 金额: $ 272.02万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY026586%2F1
• 关键词: HEXAGEN; Harnessing; haematopoietic; stem; cell

Haematopoietic Stem Cell (HSC) Gene Therapy (GT) is no longer an experimental treatment, but a medicinal product and the only curative option for many monogenic inherited disorders. It relies on genetic correction of HSCs, the only cells driving lifelong blood production when grafted back into the patient. Owing to decades of optimization, current protocols efficiently correct HSC genetic defects. However, they fail to maintain HSC function during the ex vivo culture step, often leading to delayed recovery or graft failure. This functional attrition is a major roadblock in guaranteeing HSC GT safety and outcomes. Why it occurs is not understood, largely because it is unclear how human HSCs resolve stress responses ex vivo. HEXAGEN will combine state-of-the-art single cell methods and HSC GT preclinical models to i) comprehensively characterise the mechanisms and functional outcomes of human HSC adaptation to ex vivo GT culture; ii) leverage this information to identify new pre-clinical strategies to deliver much larger numbers of highly regenerative HSCs to patients.HEXAGEN capitalises on our recent discovery of an early ex vivo adaptation phase, occurring before HSC GT gene correction, during which HSCs sharply and irreversibly lose function and remodel their molecular networks. First, we will use single cell -omics technologies across molecular scales to derive a functionally annotated and temporally resolved map of HSC adaptation to GT and preclinical HSC expansion conditions. Second, using mRNA electroporation and analysis of HSC quality control networks, we will identify specific adaptation driven processes that determine irreversible HSC functional changes. Finally, we will devise novel methods to minimise ex vivo loss of HSC function and test them in HSC GT preclinical xenograft models. We estimate that increasing the number of HSCs reinfused will lower costs and significantly improve safety and outcomes of HSC GT, agnostic of the target disease.

造血干细胞（HSC）基因治疗（GT）不再是一种实验性治疗，而是一种药物产品，也是许多单基因遗传性疾病的唯一治疗选择。它依赖于HSC的遗传校正，当移植回患者体内时，HSC是唯一驱动终身血液生产的细胞。经过几十年的优化，目前的方案有效地纠正了HSC的遗传缺陷。然而，它们在离体培养步骤期间不能维持HSC功能，通常导致延迟恢复或移植失败。这种功能损耗是保证HSC GT安全性和结果的主要障碍。其发生的原因尚不清楚，主要是因为尚不清楚人类HSC如何在体外解决应激反应。HEXAGEN将联合收割机结合最先进的单细胞方法和HSC GT临床前模型，i）全面研究人HSC适应体外GT培养的机制和功能结果; ii）利用这些信息来确定新的临床前策略，以向患者提供更多数量的高度再生的HSC。HEXAGEN利用我们最近发现的早期离体适应期，发生在HSC GT基因纠正之前，在此期间HSC急剧且不可逆地失去功能并重塑其分子网络。首先，我们将使用跨分子尺度的单细胞组学技术来推导HSC适应GT和临床前HSC扩增条件的功能注释和时间分辨图。第二，使用mRNA电穿孔和HSC质量控制网络的分析，我们将确定特定的适应驱动的过程，决定不可逆的HSC功能变化。最后，我们将设计新的方法来最大限度地减少HSC功能的离体损失，并在HSC GT临床前异种移植模型中对其进行测试。我们估计，增加HSC回输的数量将降低成本，并显着改善HSC GT的安全性和结局，而不知道目标疾病。