Clinical and Translational Framework for HSPC Gene Therapy Across Multiple Rare Disorders

Background Hematopoietic stem cell gene therapy (HSC-GT) represents a promising therapeutic strategy for a subset of rare and ultra-rare diseases characterized by high unmet medical need, including inborn errors of immunity and neurometabolic disorders with central nervous system involvement. By combining the long-term repopulating capacity of HSCs with stable genetic modification, HSC-GT offers the potential for durable therapeutic benefit following a single intervention. However, its clinical translation is challenged by biological complexity, demanding manufacturing requirements, evolving regulatory frameworks, and limited economic sustainability, particularly in ultra-rare indications. Methods and Results This Thesis adopts a platform-based, translational approach to support the progression of multiple HSC-GT programs from preclinical development toward early-phase clinical application within an academic, cross-border collaboration. Three representative diseases were addressed: neuronal ceroid lipofuscinosis type 1 (CLN1), mucopolysaccharidosis type II (MPS II), and MUNC13-4 deficiency (familial hemophagocytic lymphohistiocytosis type 3). The work focused on the integration of disease biology, preclinical evidence, chemistry, manufacturing and controls (CMC) development, regulatory strategy, and clinical protocol design. Key activities included completion and validation of preclinical packages, technology transfer to a centralized GMP manufacturing facility, optimization and scale-up of manufacturing processes, exploration of alternative HSC sources for research use, regulatory interactions with national authorities, and adaptation of clinical trial designs to account for disease-specific endpoints, patient populations, and sustainability across different healthcare systems. Conclusions This Thesis illustrates how coordinated academic platforms can bridge the gap between preclinical innovation and clinical translation in HSC-GT for rare diseases with high unmet needs. While clinical efficacy outcomes are beyond the temporal scope of this work, the results provide concrete evidence of translational advancement, technical feasibility, and regulatory maturation across all three programs, supporting this platform-based academic collaboration as a viable strategy to enable early clinical development. Continued investment in shared infrastructures, adaptive regulatory pathways, and long-term translational expertise will be essential to expand patient access and to broaden the future impact of HSC gene therapy.