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A groundbreaking study has demonstrated the potential of lentiviral vector (LV)–based gene therapy using CD34+ hematopoietic stem cells (HSCs) in treating severe hemophilia A. The therapy resulted in stable factor VIII expression, with higher vector copy numbers correlating to increased factor VIII activity. Notably, all five participants in the study experienced zero bleeding events throughout the follow-up period, indicating possible long-term efficacy.
Study Methodology
The single-center study was conducted on five participants aged 22-41 years with severe hemophilia A, who did not have factor VIII inhibitors. Researchers administered CD68-ET3-LV–transduced autologous CD34+ HSCs at doses ranging from 5.0×10⁶ to 6.1×10⁶ per kg following myeloablative conditioning.
The primary safety endpoints included engraftment and regimen-related toxic effects, while efficacy endpoints focused on factor VIII activity levels and the annualized bleeding rate. The follow-up period extended to September 30, 2024, with a median follow-up of 14 months (range: 9-27 months).
Key Findings
- Vector copy numbers in the final drug product varied from 0.6 to 1.0 copies per cell in group 1 and from 0.6 to 2.2 copies per cell in group 2.
- Median factor VIII activity levels post-day 28 ranged from 1.7-5.2 IU per deciliter in group 1 and 19.3-39.9 IU per deciliter in group 2.
- All participants maintained an annualized bleeding rate of zero over a cumulative follow-up of 81 months.
- Successful engraftment was observed, with a median time to neutrophil engraftment of 11 days and platelet engraftment of 15 days.
Clinical Implications
This study highlights the promise of LV-based gene therapy in ensuring stable factor VIII expression, which could revolutionize hemophilia A treatment. The findings reinforce the link between factor VIII activity and peripheral-blood vector copy numbers, underscoring the therapy’s potential clinical impact.
Study and Funding Sources
The research, led by Dr. Alok Srivastava from the Christian Medical College in Vellore, India, was published in The New England Journal of Medicine on December 9. Funding was provided by the Department of Biotechnology, Ministry of Science and Technology, Government of India, the National Institutes of Health, and Hemophilia of Georgia.
Limitations and Future Directions
As the study involved only five participants and was conducted at a single center, the results are qualitative and based on data inspection without statistical analysis. Additionally, the median follow-up of 14 months remains relatively short. Larger, multicenter trials with extended follow-up periods will be necessary to validate these findings.
Disclaimer
This article is for informational purposes only and does not constitute medical advice. Individuals should consult healthcare professionals before considering any treatment options based on research findings.
