Dr. San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute Milan, Lombardia, Italy
Abstract: Hematopoietic Stem Cell (HSC) gene therapy (GT) has the potential to provide lifelong reconstitution of the hematopoietic system with gene-corrected cells. However, the impact of underlying genetic diseases, replication stress, and aging on hematopoietic reconstitution and lineage specification remains incompletely understood. In this study, we analyzed hematopoietic reconstitution in 53 patients treated with lentiviral HSC-GT for conditions including metachromatic leukodystrophy (MLD), Wiskott-Aldrich syndrome (WAS), and β-thalassemia (β-Thal) over a follow-up period of up to eight years. Vector integration sites were used as markers of clonal identity. Our findings revealed that long-term hematopoietic reconstitution was supported by 770 to 35,000 active HSCs. While approximately 50% of transplanted clones demonstrated multilineage potential across all conditions, the remaining clones exhibited disease-specific patterns of lineage output and long-term commitment: predominantly myeloid for MLD, lymphoid for WAS, and erythroid for β-Thal, particularly in adult patients. These results suggest that HSC clonogenic activity, lineage output, long-term lineage commitment, and rates of somatic mutations are shaped by several factors, including the underlying disease, patient age at the time of therapy, the extent of genetic defect correction, and the hematopoietic stress imposed by the inherited condition. This indicates that HSCs adapt dynamically to the pathological environment during hematopoietic reconstitution.
Funding Source:
Clinical Trial ID number: NCT01560182; NCT01515462; NCT02453477
