Table 4.

Therapies with curative intent

Allogeneic hematopoietic stem cell transplant
HLA-matched sibling donor	Standard approaches rely on myeloablative conditioning with overall and disease-free survival rates in the 90% range for children and young adults with SCD Reduced intensity and reduced toxicity, nonmyeloablative regimens offer alternative strategies to achieve stable, mixed chimerism in adults with SCD
Umbilical cord donor	Cord units from related or unrelated donors represent alternative sources of hematopoietic stem cells for children with SCD; routine use is limited by lower total cell dose Units from unrelated donors are associated with higher risk of graft rejection and graft-versus-host disease
HLA-matched unrelated donor	Demographics of current donor pool limit this option for Black patients with SCD High rates of acute and chronic graft-versus-host disease remain a significant challenge
Haploidentical donor	Haploidentical donors offer most accessible donor type for children and adults with SCD Strategies focused on T-cell depletion using post-transplant cyclophosphamide have improved engraftment rates and reduced graft-versus-host disease
Autologous gene-based therapy
Gene addition or transfer	Lentiviral-based vector encodes modified β- or γ-globin transgenes to increase anti-sickling hemoglobin production Lentiviral-based vector transfers short-hairpin RNA (shRNA) targeting BCL11A to increase γ-globin expression Transduction efficiency is high with current vectors Concerns remain about risk of insertional oncogenesis and long-term high-level expression
Gene editing	Genome editing focuses on correction of SCD mutation, downregulation of BCL11A or mimicking of hereditary persistence of fetal hemoglobin (HPFH) mutations Strategies rely on CRISPR-Cas9 technology or engineered DNA-cleaving enzymes such as zinc-finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs)