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June 10, 2002 -- No. 332

New gene therapy treatment works in mice with hemophilia A

By ROBIN L. ARNETTE
UNC School of Medicine

CHAPEL HILL -- Scientists at the University of North Carolina at Chapel Hill have successfully treated mice with hemophilia A using a new approach to gene therapy: RNA trans-splicing.

The experimental procedure repairs a mutated section of the gene responsible for hemophilia A, a hereditary bleeding disorder.

Dr. Hengjun Chao, a research assistant professor at the UNC School of Medicine’s Gene Therapy Center, will present the new research Saturday (June 8) in Boston at the Presidential Symposium of the American Society of Gene Therapy’s annual meeting.

Hemophilia A is a sex-linked congenital disease, occurring in one of 5,000 to 10,000 live males and caused by a defect in coagulation factor VIII. The mutation renders the factor VIII gene non-functional, resulting in recurrent, non-predictable, spontaneous bleeding into major joints and soft tissues. Currently, the disorder is treated with injections of factor VIII protein in response to bleeding incidents. Conventional approaches to gene therapy have not proven successful against hemophilia A, partially due to difficulties involved in packaging and delivering the large factor VIII gene.

This new study in mice with hemophilia A was conducted in collaboration with scientists from Intronn Inc., of Rockville, Md., where RNA trans-splicing was pioneered. A pre-trans-splicing molecule, or PTM, was injected into some of the mice. The molecule, or cassette, is designed to produce RNA that binds and splices onto the existing faulty RNA, correcting it. The corrected RNA then encodes for the normal factor VIII protein.

"Preliminary data using the hemophilia A mice are very encouraging," said Chao, "After injecting hemophilia A mice with the PTM cassette, factor VIII levels in the blood rose from lower than 1 percent to a maximum of 20 percent of normal factor VIII activity. These levels of activity corrected the bleeding tendency of the hemophilia A mice, thus protecting the mice from a trauma challenge, which is usually lethal to untreated hemophilia A mice.

"If the technology is proven effective in humans, it would provide a more permanent treatment for hemophilia A."

The RNA trans-splicing method offers several advantages over conventional DNA gene therapy, said Dr. Christopher Walsh, assistant professor of medicine at UNC and principal investigator of the study.

"Among these, only a mutated segment of the gene is repaired rather than the entire gene. Also, very large pieces of DNA cannot be effectively packaged and delivered using conventional DNA viral vector therapy. This new gene therapy tool will help treat hemophilia A, as well as a host of other genetic diseases such as cystic fibrosis, sickle cell anemia, muscular dystrophy and some forms of cancer."

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Note: Contact Chao at (919) 966-9117 or hchao@med.unc.edu.

School of Medicine contact: Les Lang at (919) 843-9687 or llang@med.unc.edu