Gene therapy achieves early success against hereditary bleeding disorder

Symptoms improved significantly in adults with the bleeding disorder hemophilia B following a single treatment with gene therapy developed by researchers at St. Jude Children's Research Hospital in Memphis and demonstrated to be safe in a clinical trial conducted at the University College London (UCL) in the U.K.

The findings of the six-person study mark the first proof that gene therapy can reduce disabling, painful bleeding episodes in patients with the inherited blood disorder. Results of the Phase I study appear in today's online edition of the New England Journal of Medicine. The research is also scheduled to be presented December 11 at the 53rd annual meeting of the American Society of Hematology in San Diego.

Four study participants stopped receiving protein injections to prevent bleeding episodes after undergoing the therapy and have not suffered spontaneous bleeding. Several have also participated in marathons and other activities that would have been difficult prior to gene therapy. The study volunteers were all treated at the Royal Free Hospital in London under the care of Edward G.D. Tuddenham, M.D., Ph.D., a pioneer in the field of blood coagulation and a study co-author.

“This is a potentially life-changing treatment for patients with this disease and an important milestone for the field of gene therapy. It could have ramifications for the treatment of hemophilia A, other protein and liver disorders and chronic diseases such as cystic fibrosis,” said first author Amit Nathwani, M.D., Ph.D., a faculty member at the UCL Cancer Institute, Royal Free Hospital and NHS Blood and Transplant (NHSBT).

Hemophilia B is caused by an inherited mistake in the gene for making a protein called Factor IX, which is essential for normal blood clotting. The gene is carried on the X chromosome. As a result, hemophilia B is almost exclusively a disease of men. About 1 in 30,000 individuals inherit the mutation.

Previous efforts to ease hemophilia B symptoms by introducing a correct copy of the gene have been unsuccessful.

The current study used adeno-associated virus (AAV) 8 as the vector to deliver the Factor IX gene along with additional genetic material into the patient's liver. AAV8 was picked because the incidence of natural infection with AAV8 is low. It belongs to a family of viruses that target liver cells but do not cause disease in humans or integrate into human DNA. Participants in the study received no immune suppressing drugs prior to gene therapy.

This approach was jointly pioneered by St. Jude and UCL, initially in the laboratory of study co-author Arthur Nienhuis, M.D, a member of the St. Jude Department of Hematology.

For this study, each patient received a one-time infusion of the vector into a vein in the arm. Two patients each were treated with escalating doses of the vector. Following treatment, Factor IX levels rose in all six patients from less than 1 percent of normal levels prior to the gene therapy to between 2 and 12 percent.

Factor IX levels increased the most in the two study volunteers who received the highest dose of the experimental vector, researchers said. After treatment, levels of the protein ranged from 3 to 12 percent in those men. Even modest increases that raise Factor IX production to more than 1 percent of normal levels have the potential to dramatically affect a patient's quality of life and reduce bleeding episodes, said the study's senior author Andrew Davidoff, M.D., chair of the St. Jude Department of Surgery.

“The first patient has been followed for the longest time, and his levels have remained at 2 percent for more than 18 months. These results are highly encouraging and support continued research. More patients are scheduled to be enrolled in future trials scheduled to begin later this year,” Davidoff said.

One of the participants who received the highest dose of the vector underwent successful, short-term steroid treatment after his liver enzymes rose slightly after the vector infusion. The rise signalled mild liver damage. The volunteer remained otherwise healthy, his Factor IX levels remain above pre-infusion levels and his liver enzymes have returned to normal. Liver enzymes also rose slightly, but remained in the normal range, for the other participant who received the highest dose of the vector. That participant also received a short course of steroids.

Researchers believe an immune response targeting the vector triggered the elevated enzyme levels. A similar response was reported in earlier gene therapy trials conducted by other investigators using a different vector.

The vector used in this study was produced at the Good Manufacturing Practices (GMP) facility on the St. Jude campus. The GMP operates under U.S. government-approved manufacturing guidelines and produces highly specialized medicines, vaccines and other products that pharmaceutical companies are reluctant to pursue. The vector can also now be produced in a similar facility at UCL.

Other authors are Savita Rangarajan, Basingstoke and North Hampshire Foundation Trust; Cecilia Rosales, Jenny McIntosh and David Linch, all of UCL Cancer Institute; Pratima Chowdary, Anja Griffioen, Anne Riddel, Jun Pie, Chris Harrington and James O'Beirne, all of Royal Free NHS Trust; Keith Smith, NHSBT; John Pasi, Bertie Glader, Pradip Rustagi and Mark May, all of Stanford University; Catherine Y.C. Ng, Junfang Zhou, Yunyu Zpense, Christopher Morton, all of Queen Mary's School of Medicine, London; James Allay, the late John Coleman, Susan Sleep, John Gray and Ulrike Reiss, all of St. Jude; John Cunningham, University of Chicago; Etiena Basner-Tschakarjan and Federico Mingozzi, both of Children's Hospital of Philadelphia and Katherine High, of the Howard Hughes Medical Institute and Children's Hospital of Philadelphia.

In the U.S., the research was funded by the National Institutes of Health, the Assisi Foundation of Memphis and ALSAC. In the U.K. the research was funded in part by The Katherine Dormandy Trust, Medical Research Council, Wellcome Trust, NHS Blood and Transplant and the UCLH/UCL NIHR Biomedical Research Centre.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is internationally recognized for its pioneering research and treatment of children with cancer and other life-threatening diseases. The hospital's research has helped push overall survival rates for childhood cancer from less than 20 percent when the institution opened to almost 80 percent today. It is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, and no family ever pays St. Jude for care. For more information, visit www.stjude.org. Follow us on Twitter @StJudeResearch.

UCL (University College London)

Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. We are among the world's top universities, as reflected by performance in a range of international rankings and tables.

Our excellence extends across all academic disciplines, from one of Europe's largest and most productive centres for medical science interacting with eleven leading London hospitals, to world-renowned centres for architecture (UCL Bartlett) and fine art (UCL Slade School).

UCL currently has 24,000 students from almost 140 countries, and more than 8,500 employees. Our annual income is over £800 million.

www.ucl.ac.uk | Follow us on Twitter @uclnews.

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