A new discovery contradicts prevailing assumptions about hemophilia and could change the treatment of hemophilia A, according to researchers.
The team discovered that the protein furin, which is required in factor IX (FIX) replacement, is not required in factor VIII (FVIII) replacement.
In fact, furin impairs clotting in hemophilia A, so gene therapy that can avoid furin processing may provide more effective treatment of hemophilia A.
Experiments in mice and dogs with severe hemophilia A supported this idea. Researchers described the experiments in JCI Insight.
“The clotting factors involved in hemophilia A and hemophilia B are very different, and this has important implications in devising new treatments,” said study author Valder R. Arruda, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.
Dr Arruda and his colleagues noted that biological differences between FVIII and FIX mean there are obstacles to effective gene therapy in hemophilia A that are not an issue in hemophilia B.
Specifically, the gene encoding FIX is much smaller than the gene for FVIII. So the gene encoding FIX is easier to fit into a vector designed to deliver the therapy to a patient.
“In gene therapy, size matters,” Dr Arruda said. “It’s important to reduce the gene package for FVIII to the smallest effective size.”
He added that, according to his group’s research, deleting the furin-recognition components both decreases the size of the gene therapy payload and strengthens its benefits for treating hemophilia A.
Dr Arruda and his colleagues bioengineered a new variant protein, FVIII-ΔF, which avoids interacting with furin. The team then used that variant in gene therapy experiments in animals with severe hemophilia A.
In mice, FVIII-ΔF gene therapy increased recombinant protein yields, enhanced clotting activity, and produced higher circulating FVIII levels when compared to B-domain-deleted FVIII.
In lab dogs with naturally occurring severe hemophilia A, FVIII-ΔF gene therapy decreased bleeding without triggering a higher level of unwanted immune reactions.
“While much work remains to be done to develop this research into clinical applications, our findings could have a promising translational impact, both for protein replacement and gene therapy,” Dr Arruda said.
“Because this variant provides more efficient bleeding control than currently available replacement drugs, while avoiding immune reactions, this could address the unmet needs of hemophilia A patients worldwide. It may also advance gene therapy for this disorder as well.”
