A review published in the Journal of Thrombosis and Haemostasis (JTH) suggests gene therapy as a potential novel approach to achieving immune tolerance induction (ITI) in patients with hemophilia A and an inhibitor to factor VIII (FVIII). The authors focus specifically on ITI for FVIII, as inhibitors in hemophilia B are significantly less frequent.
Historically, ITI is achieved through long term and uninterrupted exposure to FVIII replacement therapies so that the body’s immune system will begin to tolerate a therapy and cease generating antibodies. Individuals who undergo ITI will receive daily infusions of factor replacement products over a period of weeks, months, or in some cases, years. While evidence suggests that this is an effective way of achieving immune tolerance, the approach has several drawbacks. The regimen requires vigilance on behalf of patients and providers to be successful, as interruptions in the consistent delivery of the therapy can derail its intended effects. Adherence to the sheer number of intravenous infusions required for ITI can become taxing for patients and families and represent a significant hardship as the process becomes more protracted. It can also be very costly, especially in cases of long-term ITI. Further, ITI fails in approximately 20% to 30% of patients with hemophilia A.
While a nonfactor, subcutaneous therapy such as emicizumab represents an effective prophylactic treatment for hemophilia patients with and without inhibitors, breakthrough bleeds and surgeries often necessitate the use of FVIII replacement therapies which can complicate the treatment picture.
The review provides a comprehensive overview of the persistent challenges and current mitigation strategies related to treating and managing patients with FVIII inhibitors. As these strategies are often associated with suboptimal outcomes or introduce additional complications, the authors introduce liver directed, AAV vector-based gene therapy as a possible novel path to tolerance. They cite several preclinical studies to discuss both its promise and the important variables associated with potential protocols related to gene therapy delivery and ITI, including timing of the gene transfer and the optimal target levels of FVIII that will achieve tolerance without raising factor levels too high.
The review also includes the critical patient perspective, encompassing real-world and quality of life implications associated with current therapeutic options related to inhibitor-related treatment. Again, cost is cited as a central challenge, as it places significant burdens of patients/families and subsequent “chronic inequities related to economic stability, food security, and the physical environment, including housing.” While successful gene therapy, posit the authors, could ease both the burden of the disease itself and the long-term cost of its treatment.
Though additional preclinical and clinical studies will be necessary to further support the gene transfer approach for reaching effective ITI in patients with FVIII inhibitors, the authors signal its full therapeutic potential.
“The liver microenvironment is a well-recognized site for establishment of tolerance to endogenously expressed proteins, and the consistent long-term delivery of FVIII provided by gene therapy may also enhance the likelihood of tolerance induction. With the recent regulatory approval in Europe of FVIII gene therapy in hemophilia A patients without inhibitors, a strong case can now be made for exploring this treatment approach in patients with FVIII inhibitors,” concluded the authors.
The full JTH paper, “A Review of the Rationale for Gene Therapy for Hemophilia A with Inhibitors: One-Shot Tolerance and Treatment?” is available in PDF format only.
Citation
Valentino LA, Ozelo MC, Herzog RW, Key NS, Pishko AM, Ragni MV, Samelson-Jones BJ, Lillicrap D. A Review of the Rationale for Gene Therapy for Hemophilia A With Inhibitors: One-Shot Tolerance and Treatment? J Thromb Haemost. 2023 May 22:S1538-7836(23)00424-5. doi: 10.1016/j.jtha.2023.05.011. Epub ahead of print. PMID: 37225021.
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