A novel gene therapy for hemophilia A that uses lentivirus vector transduced autologous hematopoietic stem cells (HSCs) safely produced stable levels of factor VIII, bypassing limitations facing adeno-associated virus (AAV)-based gene therapies.
“The early results of this clinical study reveal a new opportunity for gene therapy for hemophilia A that can be offered to all patients, possibly at an early age, and that results in sustained expression of therapeutic levels of factor VIII,” wrote the authors of a study assessing the novel gene therapy that was published in the
New England Journal of Medicine. The single-center study involved five participants (ages 22 to 41 years) with severe hemophilia A without factor VIII inhibitors.
Participants receiving the CD68-ET3-LV–transduced autologous CD34-positive HSCs (at doses of 5.0×106 to 6.1×106/kg of body weight) showed a median factor VIII activity level of 5.2 IU/dL in group 1 and 1.7 IU/dL in group 2 after day 28 through the last follow-up visit.
For two patients in group 1, peripheral-blood vector copy numbers were 0.2 and 0.1 copies per cell, respectively. Among three patients in group 2, the median factor VIII activity levels were 37.1 IU/dL, 19.3 IU/dL and 39.9 IU/dL, respectively, with peripheral-blood vector copy numbers of 4.4, 3.2, and 4.8 copies/cell, respectively. Importantly, the annualized bleeding rate was zero for all five participants, with a cumulative follow-up of 81 months (and a median follow-up of 14 months). Before gene therapy, all participants reported an annualized bleeding rate of at least 20 events.
The authors noted that, “an AAV vector–based hepatocyte-directed gene therapy has been approved for the treatment of hemophilia A [in Europe and the United States]. However, this technology has several limitations, including variable initial expression of factor VIII and a gradual decline of expression after the first 6-12 months.”
In an accompanying
editorial, Johnny Mahlangu, MBBCh, of the University of the Witwatersrand in Johannesburg, South Africa, wrote, “The use of lentiviral vector to deliver the factor VIII gene therapy not only overcomes the barrier with respect to preexisting anti-AAV antibodies but also opens the door for many more patients, including pediatric patients, to receive gene therapy.”
The new therapy involves the collection of autologous CD34+ HSCs, which were transduced with CD68-LV-ET3. This lentiviral vector includes a new F8 transgene (ET3) with a myeloid-directed CD68 promoter. Transduced HSCs were transplanted into recipients following myeloablative conditioning. The treatment was assessed for safety and efficacy.
More specifically, CD34+ cells were mobilized with granulocyte colony-stimulating factor (G-CSF) and plerixafor to obtain an adequate number of autologous CD34+ peripheral-blood stem cells, defined as more than 5×106 CD34+ cells per kilogram of body weight.
For group 1 patients, the enriched CD34+ HSCs were transduced with the lentiviral vector CD68-ET3-LV using a double-exposure transduction protocol. However, based on a review of these two patients, investigators modified the transduction protocol for the three remaining participants to include a transduction enhancer and a single exposure to the vector.
The duration of severe neutropenia was 7 to 11 days, and severe thrombocytopenia lasted 1 to 7 days.
