A Paradigm Shift in Hemophilia Care: The Promise of Gene Therapy.

Abstract

Introduction: The discovery of the gene as the primary unit of inheritance marked the beginning of intensive research into targeted genome modifications for treating rare genetic diseases. Despite conventional approaches such as continuous factor replacement or novel non-factor therapies, the need for a one-time infusion and long-term sustenance of clotting factors is evident. This review focuses on gene therapies discovered to treat patients with hemophilia. This narrative review seeks to highlight the current potential of gene therapies for hemophilia, elucidate their mode of action, and assess their long-term effectiveness and clinical significance.

Methods: A literature search in PubMed, Embase, Google Scholar, and Scopus databases was done using search terms like gene therapy, viral vectors, Roctavian, hemophilia, etranacogene dezaparvovec, AAV, and FIX-Padua variant.

Results: Following intensive clinical trials and successful outcomes, the currently available FDAapproved gene therapies include valoctocogene roxaparvovec (Roctavian) for hemophilia A and etranacogene dezaparvovec (Hemgenix), and fidanacogene elaparvovec (Beqvez) for hemophilia B, and an antibody-based therapy, Marstacimab (Hympavzi) for both hemophilia A and B.

Discussion: Decades of clinical research on introducing gene therapy as a potential therapy for hemophilia A and B have paved the way for successful discovery to overcome the long-term burden of factor replacement and other adjunct therapies. Gene therapy has shown persistent success in hemophilia, with clinical trials demonstrating long-term expression of functional clotting factors (Factor VIII or IX). This has reduced bleeding episodes remarkably and the need for regular factor replacement therapy. Yet the drugs need to be studied further to assess long term safety and efficacy following administration.

Conclusions: Gene therapy has shown new possibilities in hemophilia, with many patients achieving near-normal levels of clotting factors and experiencing a significant reduction in bleeding episodes. However, challenges remain, including potential declines in Factor VIII levels over time, immune responses to viral vectors, and high treatment costs. Ongoing research is focused on improving durability, expanding eligibility, and exploring alternative delivery methods.