Researchers Make Gene Therapy Breakthrough in Dogs with Factor VII Deficiency

University of North Carolina

A team of researchers from the University of North Carolina (UNC) and The Children’s Hospital of Philadelphia (CHOP) recently reported the successful application of gene therapy in dogs with factor VII (FVII) deficiency. This represents a significant advance, as demonstrating the safety and efficacy of a novel therapy in large animal studies is a standard precursor to eventual clinical trials in humans.

FVII deficiency is a rare bleeding disorder with an incidence of 1 in 300,000 to 500,000, since both parents need to carry the gene in order to pass it on to their children. The condition, which affects men and women equally, is characterized by inadequate production of the FVII clotting protein. Babies are often diagnosed within the first six months of life after sustaining an intracranial hemorrhage or bleeding in the gastrointestinal tract. People with the more severe form of FVII deficiency often experience joint and muscle bleeds, easy bruising and bleeds after surgery. Bleeding can also occur in the skin, mouth, nose and genitourinary tract, while women often experience severe menorrhagia (prolonged, heavy periods.) The primary treatment for FVII deficiency is recombinant factor VIIa.

The study, “Sustained Correction of FVII Deficiency in Dogs Using AAV-Mediated Expression of Zymogen FVII,” was published in the Feb. 4 issue of Blood. The senior investigator was Paris Margaritis, D.Phil., head researcher at CHOP and research assistant professor of pediatrics at the University of Pennsylvania’s Perelman School of Medicine. Leading the UNC team was Tim Nichols, M.D., professor of medicine and pathology at the UNC School of Medicine.

To begin, Margaritis cloned the canine factor VII gene and enclosed that genetic material inside adeno-associated viruses (AAVs). These viruses act as delivery vehicles, or vectors, to carry the genetic material into living cells to sustain therapeutic effect without causing disease or triggering significant immune responses. In this case, the AAVs are designed to elicit the production of the FVII. Nichols and his colleagues then treated four FVII deficient dogs with a single injection of the therapy, administering different amounts of AAVs in each of the animals.

They found that the amount of factor VII generated was directly proportional to the amount of AAVs given to the individual dogs. Nichols’s team also monitored the dogs’ progress over a period of three years and found that they all produced FVII levels that were sufficiently therapeutic—this is particularly encouraging for investigators because the amount of FVII necessary to achieve a sustained therapeutic effect in dogs correlates closely to that for humans. “This work is very exciting and promising,” said Nichols. “The FVII-deficient dogs tolerated the initial gene therapy infusions very well and have had no adverse side effects over several years of follow up. In other related studies in dogs with hemophilia B (FIX), similar positive findings have translated to people with hemophilia B.”  

In addition, blood, kidney and liver function tests all showed that therapy was safe and did not trigger an unwanted immune response. The next step will be to conduct clinical trials in humans. “The table is now set to propose clinical trials that would treat people who suffer from FVII deficiency,” concluded Nichols.