by Justin Jackson , Medical Xpress

Credit: Pixabay/CC0 Public Domain

Research led by Christian Medical College in Vellore, India, has demonstrated the successful use of lentiviral vectors to deliver gene therapy for patients with severe hemophilia A. The study presents a potential alternative to adeno-associated virus (AAV)-mediated gene therapy, addressing the exclusion of patients with preexisting anti-AAV antibodies.

Severe hemophilia A is caused by a genetic absence or variant in genes needed to produce blood-clotting factor VIII, leading to prolonged bleeding and joint damage. Current treatments, including replacement therapies with AAV-based gene therapy, have either not been entirely successful, diminished over time or could only be used in patients without anti-AAV antibodies.

To overcome these barriers, researchers explored lentiviral vectors, which integrate into the genome and bypass AAV-specific limitations. In the study, “Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A,” published in The New England Journal of Medicine, researchers used a lentiviral vector to deliver gene therapy to five patients with hemophilia A.

After treatment, all five had stable levels of factor VIII in their blood, with no serious safety concerns. During the follow-up observation period, none of the patients had uncontrolled bleeding.

The follow-up period varied between patients from 9 to 27 months with a median of 14 months. The reason for this is unclear and not explicitly stated. The study might have an arbitrary data collection end date separate from when the patients received treatment. If this is the case, earlier treatment dates within the study period would then lead to longer follow-up durations. Regardless of the reason for the disparity, it makes the longevity of effect data beyond the shared observation period less impactful.

Overall results of the lentiviral gene therapy show promise in overcoming a limitation of AAV-mediated approaches with the ability to bypass anti-AAV antibodies.

There may be some critical complications to lentiviral gene therapies in general that would first need to be resolved, according to an editorial, “Could Lentivirus Overcome the AAV Gene-Therapy Challenges in Hemophilia A?” also published in The New England Journal of Medicine.

Concerns are raised regarding integration of lentivirus into the host genome. Previous studies have linked lentiviral vectors to blood cancer with a greater than 10% risk factor, with some major confounders.

In the previous study, mentioned in the editorial, 7 of 67 patients treated with lentiviral vector–delivered gene therapy developed hematologic cancers due to gene insertions. The confounder is that, in the previous study, all 7 had received busulfan and cyclophosphamide conditioning, a regimen known to be leukemogenic.

In the current research, treosulfan was used instead of busulfan in the conditioning regimen, potentially countering the confounding of the previous study.

With such a small sample size and short follow-up time, more research will be required before lentiviral gene therapy can be considered entirely safe, though there may be enough of a cost benefit for some patients currently suffering from severe hemophilia A.

More information: Alok Srivastava et al, Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A, New England Journal of Medicine (2024). DOI: 10.1056/NEJMoa2410597

Johnny Mahlangu, Could Lentivirus Overcome the AAV Gene-Therapy Challenges in Hemophilia A?, New England Journal of Medicine (2024). DOI: 10.1056/NEJMe2414214

Journal information:New England Journal of Medicine

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