Gene therapy for rare bleeding disorder achieves proof-of-concept

January 20, 2016, Children's Hospital of Philadelphia

Hematology researchers have used a single injection of gene therapy to correct a rare bleeding disorder, factor VII deficiency, in dogs. This success in large animals holds considerable potential for a safe, effective and long-lasting new treatment in humans with the same bleeding disorder.

"Our finding has great clinical relevance for patients with factor VII deficiency," said study leader Paris Margaritis, D. Phil., a hematology researcher at the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (CCMT) at The Children's Hospital of Philadelphia (CHOP). "These have the type of mutation found in the majority of patients with this disorder, so this approach could lead to a sustained gene therapy in people."

The study appeared online Dec. 23 in Blood.

The Margaritis team collaborated with University of North Carolina (UNC) scientists, led by Tim Nichols, M.D., professor of Medicine and Pathology at the UNC School of Medicine.

Factor VII deficiency is rare, found in about one in 300,000 to one in 500,000 people. Because a gene mutation impairs normal production of a blood clotting factor, patients may suffer excessive bleeding in the central nervous system or GI tract, or after surgery or an injury. Female patients may suffer excessive menstrual bleeding.

Factor VII (FVII) deficiency has a range of severity, with about 40 percent of patients having severe disease. They are most commonly treated with regular infusions of clotting factor. Unlike hemophilia, a better-known that predominantly affects males, factor VII deficiency strikes males and females equally.

Gene therapy proposed for bleeding disorders involves introducing DNA carrying the code to produce the specific clotting factor lacking in patients. Researchers at CHOP and elsewhere have bioengineered an adeno-associated virus (AAV), which does not cause disease, as a vector to deliver DNA into cells where it can express enough factor to make the blood clot normally. Over the past 15 years, CHOP hematology researchers have performed of gene therapy for hemophilia B that have helped define efficacy and dosing levels in humans.

The CCMT at CHOP houses a clinical-grade laboratory that manufactures gene therapy vectors, including the AAV vectors used in the current study. Margaritis, a member of the CHOP group long engaged in hemophilia research, currently leads a laboratory focused on factor VII deficiency as well as hemophilia.

"We developed a unique animal model of this disease after identifying dogs with naturally occurring factor VII deficiency," said Margaritis. "Our investigations enabled us to design the corrective gene to insert into our virus vector in the current study."

The CHOP team collaborated with scientists at UNC who have a long-established colony of dogs for hematology research. Based on previous work by Margaritis, the UNC team identified dogs for this gene therapy study.

Nichols, the director of UNC's Francis Owens Blood Research Laboratory, characterized factor VII deficiency in four individual dogs. Using the AAV vectors supplied by Margaritis, Nichols injected the dogs with varying dosages and monitored their health outcomes and biological markers over several years.

The treated dogs had expressed levels of VII that would be therapeutic in humans, with long-term stability. In one dog, the effects persisted nearly three years. Based on kidney function, liver function, and blood measurements in the dogs, the treatment was safe, and did not elicit unwanted immune responses.

The current study sets the stage for clinical trials in humans. This gene therapy may especially benefit young children with severe bleeding from factor VII deficiency, such as patients receiving care in CHOP's hematology program.

"This work is very exciting and promising," said Nichols, who added, "The FVII-deficient dogs tolerated the initial 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, similar positive findings have translated to people with hemophilia B." Both Nichols and Margaritis agreed: "The table is now set to propose clinical trials that would treat people who suffer from FVII deficiency."

Explore further: Study bolsters 'turbocharged' protein as a promising tool in hemophilia gene therapy

More information: "Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII," Blood, published online Dec. 23, 2015. doi.org/10.1182/blood-2015-09-671420

Related Stories

Study bolsters 'turbocharged' protein as a promising tool in hemophilia gene therapy

March 12, 2015
Using gene therapy to produce a mutant human protein with unusually high blood-clotting power, scientists have successfully treated dogs with the bleeding disorder hemophilia, without triggering an unwanted immune response. ...

New gene therapy targets hemophilia

December 11, 2013
Researchers at the UNC School of Medicine and the Medical College of Wisconsin found that a new kind of gene therapy led to a dramatic decline in bleeding events in dogs with naturally occurring hemophilia A, a serious and ...

Long lasting anti-hemophilia factor safe in kids

April 24, 2015
Children with hemophilia A require three to four infusions each week to prevent bleeding episodes, chronic pain and joint damage. The effect on quality of life can be significant, due to time and discomfort associated with ...

Coagadex approved for rare clotting disorder

October 21, 2015
(HealthDay)—Coagadex (coagulation Factor X) has been approved by the U.S. Food and Drug Administration as the first coagulation factor replacement therapy for people with a rare blood disorder known as hereditary Factor ...

Gene therapy helps patients with hemophilia B

December 13, 2011
(Medical Xpress) -- An experimental gene therapy technique boosted the production of a vital blood clotting factor in six people with hemophilia B, according to new research supported by the National Institutes of Health. ...

Antibody for severe hemophilia a may reduce injections needed to prevent bleeding

December 1, 2015
An antibody engineered to prevent excessive bleeding in patients with severe hemophilia A may be safe and effective, and require fewer injections than existing options, according to a first-in-human study of the treatment ...

Recommended for you

Age-related increase in estrogen may cause common men's hernia

October 16, 2018
An age-related increase in estrogen may be the culprit behind inguinal hernias, a condition common among elderly men that often requires corrective surgery, according to a Northwestern Medicine study was published Oct. 15 ...

New findings cast light on lymphatic system, key player in human health

October 16, 2018
Scientists at the Oklahoma Medical Research Foundation have broken new ground in understanding how the lymphatic system works, potentially opening the door for future therapies.

New model suggests cuffless, non-invasive blood pressure monitoring possible using pulse waves

October 16, 2018
A large team of researchers from several institutions in China and the U.S. has developed a model that suggests it should be possible to create a cuffless, non-invasive blood pressure monitor based on measuring pulse waves. ...

Discovery of inner ear function may improve diagnosis of hearing impairment

October 15, 2018
Results from a research study published in Nature Communications show how the inner ear processes speech, something that has until now been unknown. The authors of the report include researchers from Linköping University, ...

Team's study reveals hidden lives of medical biomarkers

October 12, 2018
What do medical biomarkers do on evenings and weekends, when they might be considered off the clock?

Widespread errors in 'proofreading' cause inherited blindness

October 12, 2018
Mistakes in "proofreading" the genetic code of retinal cells is the cause of a form of inherited blindness, retinitis pigmentosa (RP) caused by mutations in splicing factors.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.