LentiGlobin Gene Therapy Possibly Safe for Severe Sickle Cell Disease

Interim data from a phase I study of LentiGlobin BB305 in patients with severe sickle cell disease (SCD) suggest that the gene therapy was safe and allowed for the production of increased amounts of anti-sickling hemoglobin (HbAT87Q). The data were presented at the 23rd Congress of the European Hematology Association by lead author Julie Kanter, MD, of the Medical University of South Carolina.

LentiGlobin BB305 is an investigational gene therapy manufactured using a new process in which autologous CD34-positive hematopoietic stem cells (HSPCs) are transduced with a lentiviral vector (BB305) that encodes for HbAT87Q. After a patient’s HSPCs are modified ex vivo, the cells are then infused back into the patient’s blood. In this protocol, investigators revamped the process with plerixafor mobilization to increase the percentage of patient stem cells that carry the corrected, functional gene.

This early-phase trial enrolled patients with severe SCD (age range = 18-42 years), defined as a history of recurrent vaso-occlusive crises, acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s.

Patients were categorized into three patient groups, each with their own collection protocol:

  • Group A: bone marrow harvesting–derived HSPCs for backup and LentiGlobin BB305 manufacturing
  • Group B: ≥2 months of red blood cell transfusions before plerixafor mobilization/apheresis for backup HSPC collection (with retained bone marrow–harvesting HSPCs for LentiGlobin BB305 manufacturing)
  • Group C: autologous CD34-positive HSPCs transduced with the BB305 lentiviral vector and backup using plerixaformobilized HSPCs

The investigators measured adverse events (AEs), cell engraftment, vector copy number (VCN), and HbAT87Q production after infusion.

A total of 10 patients received LentiGlobin BB3305 at a median dose of 2.1×106 cells/kg (range = 1.6×106-5.1×106 cells/kg).

After a median follow-up of 21.6 months (range = 17.8-26.7 months), the investigators reported the following:

  • median peripheral blood VCN (copies per diploid genome): 0.1 (range = 0.1-0.2)
  • total hemoglobin: 9.7 g/dL (range = 7.5-10.9 g/dL)
  • HbAT87Q levels: 0.7 g/dL (range = 0.5-2.0 g/dL)

In group C (the group that received LentiGlobin BB3305 with the amended study protocol), six of 11 patients completed the plerixafor mobilization/apheresis process, with a high transduction success rate: 78 to 88 percent of CD34-positive were successfully transduced. By three months post-infusion, four of these patients were producing 3 to 6 g/dL of HbAT87Q, “making over 30 percent anti-sickling HbAT87Q,” the researchers wrote.

Following bone-marrow harvesting, investigators observed 17 grade 3-4 AEs in five patients; another five grade 3-4 AEs were observed in three patients following plerixafor mobilization/ apheresis. At last follow-up, there were no observed incidences of graft failure or grade 3-4 infusion-related toxicities associated with LentiGlobin BB305. Also, according to the researchers, the rate of grade 3-4 AEs following LentiGlobin BB3305 was consistent with those observed after myeloablative conditioning.

Limitations of the study include its relatively small patient population and the short follow-up.

While these results were encouraging, Dr. Kanter noted that these results are still early. “Considering this is an interim evaluation of an ongoing study, I don’t think we’re yet ready to say these findings will play a role in current clinical care,” she told ASH Clinical News. “At the moment, gene therapy may have a potential curative role for severe cases of SCD, but I don’t believe we’ve reached the point for the routine use of gene therapy for reversing some of the abnormal findings in SCD, such as cardiac or renal dysfunction, any time soon.”

The researchers reported no conflicts of interest.


Kanter J, Thompson A, Mapara M, et al. Recent progress in gene therapy for severe sickle cell disease: updated interim results from a phase 1 clinical study of lentiglobin gene therapy. Abstract #S836. Presented at the 23rd Congress of the European Hematology Association, June 16, 2018; Stockholm, Sweden.