Enhanced FVIII hemophilia A gene therapy may control bleeds better
Approach now is to provide normal F8 gene, which offers diminishing returns
A gene therapy designed to provide hemophilia A patients with a highly functional version of factor VIII (FVIII), the blood clotting protein they lack, could offer more sustained bleed control than existing gene therapies, preclinical research suggests.
The current approach in hemophilia A gene therapy is to provide a healthy, normal version of the F8 gene that encodes FVIII, letting the body make more of the clotting protein on its own. Evidence suggests FVIII production may diminish over time, however, limiting the therapy’s ability to provide sustained bleed control.
The gene therapy FVIII-QQ was able to overcome that limitation in mice, keeping FVIII activity high over time and enabling better bleed control.
“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,” Lindsey George, MD, of the Children’s Hospital of Philadelphia and the study’s senior author, said in a press release. “We envision these insights will provide a path forward for future research, along with avenues for clinical translation to help hemophilia A patients.”
The findings were detailed in the study, “Pre-clinical evaluation of an enhanced-function factor VIII variant for durable hemophilia A gene therapy in male mice,” in Nature Communications.
In hemophilia A, F8 gene mutations lead to a lack of functional FVIII, leaving patients vulnerable to spontaneous, excessive, and prolonged bleeding episodes.
Last year, U.S. regulators approved Roctavian (valoctocogene roxaparvovec-rvox), the first gene therapy for hemophilia A. The one-time treatment provides a functional version of F8, packaged into a viral carrier called an adeno-associated virus (AAV) that helps it be taken up by liver cells.
FVIII-QQ may be promising next-gen gene therapy
Some studies suggest the therapy enables normal or near-normal FVIII activity at first, but FVIII levels drop over time, causing the protein’s activity to be in the range of mild or moderate hemophilia in the long run. Other studies show the treatment leads to stable FVIII activity, but still within the range of mild or moderate hemophilia.
Either way, that means current gene therapy approaches may not be able to restore FVIII levels to where completely normal bleed control is possible over the long term.
One possible way to overcome such a limitation is to deliver a gene encoding the production of an enhanced version of FVIII that’s more functional than normal and allow normal bleed control even at lower FVIII levels. This is a strategy not unlike that used in approved gene therapies for hemophilia B.
Researchers developed an FVIII variant called FVIII-QQ that’s designed to bypass certain processes that normally inactivate FVIII, thereby having higher function than normal. Here, the scientists explored whether a gene therapy providing FVIII-QQ might be a promising next-generation strategy for hemophilia A.
When a mouse model of hemophilia A was treated with a standard gene therapy, FVIII levels diminished over time, as did the number of copies of its AAV carrier in the liver. The researchers believe this loss of AAV, which is necessary for the therapy’s function, is what underlies the loss of FVIII activity in Roctavian.
In a series of experiments, the scientists showed that a gene therapy designed to provide FVIII-QQ, although still packaged in an AAV vector, could resist inactivation and had enhanced activity relative to normal FVIII.
In mice, FVIII-QQ gene therapy led to better bleed control relative to a standard FVIII gene therapy, despite achieving similar clotting protein levels overall. The enhanced gene therapy didn’t increase the risk of blood clots in the animals.
Researchers believe FVIIII-QQ could help enhance the therapeutic effects of hemophilia A gene therapy. Instead of needing more FVIII protein for bleed control, which requires higher doses of the AAV vector that can cause toxicity, the approach makes smaller amounts of FVIII more functional, enabling complete and sustained bleed control.
“These results address the molecular basis of a major limitation of [hemophilia A] AAV gene therapy and provide a rationally bioengineered solution,” the researchers wrote.
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