New Study Shows That Lentiviral Gene Therapy Has The Potential to Successfully Treat Patients with Severe Hemophilia A

Hemophilia is an X-linked recessive inherited bleeding disorder caused by genetic defects in coagulation factor VIII or coagulation factor IX. It is divided into two main types: hemophilia A (F VIII deficiency) and hemophilia B (F IX deficiency). In a new study, researchers from Christian Medical College in Vellore, India, and other research institutions found that lentiviral vectors can be successfully used to provide gene therapy for patients with severe hemophilia A. They provide a potential alternative to adeno-associated virus (AAV)-mediated gene therapy, solving the problem of excluding patients with pre-existing anti-AAV antibodies from gene therapy. The relevant research results were published online in the New England Journal of Medicine on December 9, 2024, with the title "Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A".

Severe hemophilia A is caused by genetic deletions or mutations in the gene needed to produce factor VIII, leading to prolonged bleeding and joint damage. Current treatments, including AAV-based gene therapy replacement therapies, are either not fully successful, become less effective over time, or can only be used in patients without anti-AAV antibodies.

To overcome these obstacles, the authors explored lentiviral vectors, which can integrate into the genome and bypass AAV-specific restrictions. In the new study, they used lentiviral vectors to deliver gene therapy to five patients with hemophilia A. After treatment, all five patients had stable levels of factor VIII in their blood without serious safety issues. During the follow-up observation period, no patient experienced uncontrolled bleeding.

Follow-up periods ranged from 9 to 27 months, with a median of 14 months. The reasons for this treatment outcome are unclear and not clearly stated. The study may have had an arbitrary end date for data collection, separate from when patients received treatment. If so, an earlier treatment date during the study would have resulted in a longer follow-up period. Whatever the reason for the difference, it would have made the longevity of the effect data outside of the shared observation period less significant.

The overall results of this lentiviral gene therapy show promise in overcoming the limitations of the AAV-mediated approach and being able to circumvent anti-AAV antibodies. However, there may be some key complications with lentiviral gene therapy that need to be addressed first. There are concerns about the integration of the lentivirus into the host genome. Previous studies have linked lentiviral vectors to blood cancers, with a risk factor of more than 10% and some major confounding factors.

In a previous study, 7 of 67 patients who received lentiviral vector-delivered gene therapy developed blood cancers as a result of the gene insertion. The confounding factor was that in this previous study, all 7 people were conditioned with busulfan and cyclophosphamide, a treatment regimen known to deplete white blood cells. In this study, these authors used treosulfan instead of busulfan in their conditioning regimen, which may offset the confounding factors present in the previous study.

Although lentiviral gene therapy may be cost-effective enough for some patients who currently have severe hemophilia A. However, due to the small sample size and short follow-up time, more research is needed before this treatment method can be considered completely safe.

Reference

Srivastava A, et al. Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A. New England Journal of Medicine, 2024.