Potential of Gene Therapy for Treating Hemophilia Demonstrated in Dog Model

A gene therapy approach was shown to cure a form of hemophilia caused by deficiency of the Factor VII coagulation protein in a dog model system.

Factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder treated by infusion of fresh-frozen plasma, plasma-derived FVII concentrates, and low-dose recombinant activated FVII. Clinical data have suggested that a mild elevation of plasma FVII levels results in improved clotting behavior.


Research dogs with a G96E missense FVII mutation (FVII-G96E) have less than 1% of normal FVII activity. Investigators at the University of North Carolina (Chapel Hill, USA) and The Children’s Hospital of Philadelphia (PA, USA) used the Western blot technique to show that these dogs had undetectable plasmatic antigen, and thus represented the most prevalent type of human FVII deficiency (low antigen/activity).

The investigators treated these animals by gene therapy using liver-directed, Adeno-associated viral (AAV) serotype VIII vector delivery of a canine FVII zymogen transgene (cFVII). The group of four dogs received escalating AAV doses.

Results published in the December 23, 2015, online edition of the journal Blood revealed that therapeutic expression of the gene (15% of normal) was attained and was stable for more than one year (ongoing) without antibody formation to the cFVII transgene. A level of gene expression more that 770% of normal was found in the dog receiving the highest AAV dose.

No evidence of pathological activation of coagulation or detrimental animal physiology was observed as platelet counts, D-dimer, fibrinogen levels, and serum chemistries remained normal in all dogs (cumulative 6.4 years). A transient and non-inhibitory IgG2 response against cFVII was seen only in the dog receiving the highest AAV dose.

“For many people living in the developing world, constant injections are not practical or at least not feasible right now; but a single injection could be,” said contributing author Dr. Tim Nichols, professor of medicine and pathology at the University of North Carolina. “We have now shown that this treatment is safe and effective for dogs with inherited factor VII deficiency. This is exciting because our other gene therapy work on bleeding disorders, such as hemophilia, has demonstrated that safety and efficacy in dogs has translated well in human clinical trials.”

Related Links:
University of North Carolina
The Children’s Hospital of Philadelphia