Sickle cell disease and hematopoietic stem cell transplantation: donor expansion, gene-modified grafts and prenatal horizons.
TL;DR
Curative SCD therapies are converging on the same challenge: establishing durable healthy hematopoiesis with acceptable toxicity, and progress will depend on graft quality, safer niche creation, patient-centred outcomes and equitable delivery.
Abstract
Purpose
OF REVIEW To review advances from the past 18 months in allogeneic hematopoietic stem cell transplantation (HSCT) and autologous gene-modified stem cell transplantation for sickle cell disease (SCD), and to relate these developments to stem cell biology, conditioning and emerging prenatal strategies. RECENT
Findings
Matched sibling HSCT remains the clinical benchmark, but recent studies show age- and regimen-dependent trade-offs between durable engraftment, graft-versus-host disease and toxicity. Haploidentical platforms using posttransplant cyclophosphamide, thiotepa or intensified low-dose irradiation have widened donor access, although infection, graft failure and chronic graft-versus-host disease remain important. Autologous CRISPR-edited and lentiviral grafts can nearly eliminate severe vaso-occlusive events, but still require stem cell collection, individualized manufacture and myeloablative conditioning. New work identifies inflammation, lineage skewing, reduced GATA1 and premature senescence as determinants of sickle stem cell fitness, while culture-sparing editing and antibody-directed conditioning offer routes to safer transplantation. SUMMARY Curative SCD therapies are converging on the same challenge: establishing durable healthy hematopoiesis with acceptable toxicity. Progress will depend on graft quality, safer niche creation, patient-centred outcomes and equitable delivery. In vivo and prenatal approaches remain preclinical and require a substantially higher maternal-foetal safety threshold.
