Findings of a new preclinical study published online in Nature Communications may help address lingering questions relevant to the long-term durability of approved hemophilia A gene therapy. The research was led by Lindsey A. George, director of clinical in Vivo Gene Therapy and attending physician with the Division of Hematology at the Children’s Hospital of Philadelphia (CHOP).
The U.S. Food and Drug Administration (FDA) approved the first adeno-associated virus (AAV) vector-based hemophilia A gene therapy (valoctocogene roxaparvovec) in the summer of 2023. AAV vectors carry the genetic codes that prompt the production of the factor VIII (FVIII) protein that is deficient in people with hemophilia A. The therapy is designed to deliver the genetic material into living cells through a one-time infusion. However, currently available follow-up data from recipients of AAV therapy suggest that FVIII levels are not consistently durable and could have a waning therapeutic effect over time.
Using mouse models, CHOP researchers observed that clotting became less effective as genetic copies of the AAV vector present in the liver decreased over time. George and her lab team subsequently developed an enhanced variant of the FVIIII protein (FVIII-QQ) that could generate sustainable therapeutic FVIII levels. FVIII-QQ is also designed to use lower doses of vector, to help forestall viral toxicities and other potential side effects associated with larger doses of AVV-based gene therapy.
The authors reported a more sustained response in hemophilia mouse models that received FVIII-QQ. With additional research investigators hope to advance this therapy to the clinical trial stage.
"This work informs the mechanism of factor VIII durability after gene transfer and supports that factor VIII-QQ may safely overcome current hemophilia A gene therapy limitations," said George. "We envision these insights will provide a path forward for future research, along with avenues for clinical translation to help hemophilia A patients."
The full article, “Pre-clinical Evaluation of an Enhanced-function Factor VIII Variant for Durable Hemophilia A Gene Therapy in Male Mice," is available here.
For more general background information, visit NBDF’s answers to frequently asked question about gene therapy.
Source: PR Newswire, September 5, 2024
