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How Can We Improve Gene Therapy to Treat Hemophilia A?
The findings:
Researchers at Children’s Hospital of Philadelphia have overcome in a preclinical model a key limitation of adeno-associated virus-mediated (AAV) gene therapy to treat hemophilia A, an inherited bleeding disorder that affects about 1 in 4,000 men worldwide. The researchers found that high levels of blood-clotting factor VIII expression — the protein that is deficient in patients with hemophilia A — correlated with low durability, meaning that the effects of gene therapy waned over time.
Their findings suggest that this occurred due to declines in the vector copy number, or the number of AAV vector genomes in targeted cells. To solve this drawback, the team engineered an enhanced function factor VIII variant, called FVIII-QQ. Data from their work with animal models showed that after receiving low doses of the FVIII-QQ variant, the models maintained sustainable levels of factor VIII function while also normalizing clot formation. This suggests that the FVIII-QQ variant may restore hemostasis and safely overcome current hemophilia A gene therapy limitations.
Why it matters:
Hemophilia A is the most common type of hemophilia, affecting more than 200,000 people worldwide. The disorder, which can cause life-threatening hemorrhage, can be treated with regular infusions of clotting factor concentrates. However, about 75% of people with hemophilia live in the developing world and do not have access to routine care.
There is currently one gene therapy approved by the U.S. Food and Drug Administration to treat hemophilia A. The in vivo gene therapy delivers the missing clotting factor via a viral vector, in which scientists remove its viral genes and infuse it with the therapeutic gene that is administered to the patient.
While initially therapeutic, the effectiveness of the licensed hemophilia A gene therapy has shown declines over time — levels of factor VIII expression dropped about 40% each year after patients received the treatment. Similar results have been observed in other hemophilia A gene therapy products currently being tested in clinical trials, and scientists have been challenged to explain and solve this barrier to long-lasting results.
Who conducted the study:
Lindsey George, MD, director of the Clinical In Vivo Gene Therapy and an attending physician in the Division of Hematology, led the study. Dr. George also led the phase 1/2 clinical trial to test the safety and efficacy of the one-time gene therapy fidanacogene elaparvovec (Beqvez®, Pfizer) for the treatment of adults with hemophilia B, which was approved by the FDA earlier this year, and a prior phase 1/2 hemophilia A gene therapy trial. Co-authors included former Postdoctoral Research Fellow Anna Sternberg, PhD; Research Associate Cristina Martos-Rus; Staff Scientist Robert Davidson; and Director of the Research Vector Core Xueyuan Liu.
How they did it:
Dr. George and colleagues investigated the durability, efficacy, and safety of FVIII-QQ as a second-generation approach to hemophilia A gene transfer to overcome limitations with current approaches. In addition to measuring the durability of factor VIII expression, the researchers investigated whether the introduction of the two amino acid changes of FVIII-QQ could potentially lead to excess clotting or a negative immune response. They found that the enhanced therapy improved durability and carried no significant risk factors.
Quick thoughts:
“We knew it was fundamentally important to understand why levels of factor VIII were declining in patients over time so that any approach moving forward would overcome this limitation,” Dr. George said. “These results address the molecular basis of a major limitation of hemophilia A gene therapy and provide a rationally engineered solution. We hope that this data will advance gene therapy and, ultimately, the care of hemophilia A patients.”
What’s next:
The Clinical In Vivo Gene Therapy group is continuing the next-phase development of in vivo gene therapy products, including improving the standard of care for patients with hemophilia A.
Where the study was published:
The study appeared in the journal Nature Communications.