Gene therapy for blood disorders loses its potency because the stem cells that make new blood die off in the lab dish before they can be returned to the patient. This functional decline is the biggest obstacle to making stem cell gene therapy safe and effective for inherited diseases such as severe combined immunodeficiency and sickle cell disease. Current protocols can correct the genetic defect in haematopoietic stem cells, but the cells lose their regenerative power during the two-to-three-day ex vivo culture step. Why this happens has remained unclear because scientists lacked a detailed picture of how human stem cells respond to the stress of being removed from the body. HEXAGEN will map that response at single-cell resolution, tracking molecular changes across time as stem cells adapt to culture conditions. The team will then test whether blocking specific adaptation-driven processes can preserve stem cell function. If successful, the project could deliver far more potent stem cells to patients, reducing graft failure, shortening recovery times, and lowering treatment costs—regardless of which genetic disease is being treated.
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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.
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