HEXAGEN Harnessing haematopoietic stem cell EX vivo Adaptation for GENe therapy

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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.