Symptomatic or prophylactic treatment of hemophilia began in the 1960s with fresh frozen plasma therapy. Over the years, treatment evolved through plasma-derived products, recombinant therapies, extended half-life products, and subcutaneous treatments. However, achieving zero bleeding has remained elusive. In 2022, gene therapies received regulatory approval, offering hope for a definitive cure for hemophilia.

Ege University joined gene therapy clinical trials in 2021. Our patient, MA, born in 1998 and diagnosed in 2000, had a childhood marked by frequent bleeding and target joint involvement despite starting prophylaxis. During gene therapy screening, he was found to be AAV5 seronegative and was invited to our clinic. Following gene therapy, it was as if he was reborn. His initial Factor VIII level of 0.1 IU/dL rose to 128 IU/dL by week 208. His HJHS score dropped from 15 to 8, and he experienced no bleeding episodes., Türkiye

Hemophilia is an ideal candidate for gene therapy because it is a single-gene disorder with a simple expression loss, even low levels of expression are clinically effective, no specific tissue or cell targeting is required and the factor is secreted directly into plasma and can be easily measured.

Initial preclinical studies (early 2000s) using both viral and non-viral methods showed limited efficacy but no significant side effects. Adequate FVIII expression was not achieved. AAV-based somatic gene therapy for hemophilia was approved and commercialized in 2022–2023. AAV is ideal for gene transfer due to its non-pathogenic nature, defective self-replication, long-term transgene expression, availability of different serotypes for different tissues. The goal of gene therapy is to insert normal FVIII/FIX genes into the liver, enabling liver cells to synthesize these clotting factors.

In the HOPE-B study, mean FIX activity was 39.0 IU/dL at 6 months (±18.7; range 8.2–97.1), 36.7 IU/dL at 24 months (±19.0; range 4.7–99.2). In the GENEr2 study,75.4% of patients had FVIII activity >5 IU/dL at year 2. However, factor expression varied significantly among patients.

Challenges in Hemophilia Gene Therapy are high sero-prevalence of AAV antibodies, potential reduction in factor synthesis due to antibody development and risk of liver damage.

The limitations of gene therapy are variable treatment response between patients, durability and applicability of the therapy, many patients already have AAV antibodies, higher vector genome doses may be required, increasing toxicity risk, immune reactions against the capsid may lead to loss of transfected hepatocytes, uncertainty in children, inhibitor-positive patients, and those with liver disease, re-dosing is not possible due to antibody development and high cost.

To overcome these limitations, new gene technologies are being explored.