The only cure available for SCD is allogeneic HSC transplantation. While children who receive an HSC transplantation from human leukocyte antigen–matched sibling donors have a success rate of greater than 90%, less than 10% of patients actually have a matched sibling donor, so this is not an option for most individuals. Further, although curative, transplants carry the associated risks of graft rejection, graft-versus-host disease, and transplant-related mortality. An alternative to matched sibling donor HSC transplantation is haploidentical transplantation, which has a cure rate of approximately 75%. Although this approach has greatly improved the problem of donor availability, patients still need to return to the clinic weekly or bimonthly for long-term immunosuppressant therapy due to the risk of graft-versus-host disease.

Although more research is needed, it is encouraging to know that gene therapy is potentially curative for SCD. Promising techniques include gene addition and gene editing therapies. Gene addition therapy with LentiGlobin gene therapy has shown promising results in HGB-206, an ongoing phase 1/2 study (NCT02140554) that I have been involved with. LentiGlobin adds a modified form of the β-globin gene (β^A-T87Q) into a patient’s own HSCs to make functional hemoglobin in the red blood cells. In the initial cohort of patients (group A), only approximately 10% of the total hemoglobin was the new hemoglobin, but after modifying the protocol for HSC collection by plerixafor mobilization followed by apheresis instead of bone marrow harvest and improving the transduction process, we were able to obtain better results (group C, a cohort of 25 patients with severe SCD). Preliminary results have been very encouraging. We recently reported that, at the last visit in 16 patients with 6 or more months of follow-up, total hemoglobin was 9.9 to 13.7 g/dL without red blood cell transfusions, with a median hemoglobin S of less than or equal to 60% and a median anti-sickling hemoglobin A^T87Q  of greater than or equal to 40%. A decrease in SCD-related complications and hemolysis in this cohort suggested a strong therapeutic benefit.

With gene editing, the most common approach is to edit the existing genes that produce fetal hemoglobin. While data from children suggest that an increase in fetal hemoglobin production by more than 30% can improve patient outcomes, additional research is needed to determine the efficacy of this approach in adults. Another issue with targeting fetal hemoglobin is that it may be challenging to differentiate between fetal hemoglobin that is produced by gene editing and fetal hemoglobin that is produced in response to bone marrow injury from the myeloablative chemotherapy. The findings of current studies are producing optimism, but long-term follow-up is needed.