November 27, 1995
Media Contact: Debbie Bangledorf
Phone: (410) 223-1731
E-mail: dbangle@welchlink.welch.jhu.edu

Johns Hopkins scientists and Targeted Genetics Corporation are set to begin a human safety trial of gene therapy for cystic fibrosis.

It is the first time that an adeno-associated virus (AAV) -- a harmless virus normally found in the body -- will be used to ferry normal copies of genes into the DNA of cells lining the nose and lungs. Cystic fibrosis (CF) is caused by defects in a gene called CFTR that hamper a protein from pumping salt and water across cells to make thin, fluid mucous.

Nearly 30,000 adults and children in the U.S. are diagnosed with CF. Severe lung disease, sinus infections and pancreatic problems are common symptoms. While advances such as antibiotics and medicines used to clear the lungs of abnormal mucus have increased life expectancy, no cure yet exists.

"We hope that the AAV transport system, or vector, will have long-lasting effects without causing harmful inflammation," says Terence Flotte, M.D., assistant professor of pediatrics and co-developer of the AAV delivery system.

"We don't know yet if the AAV vector will allow therapeutic amounts of the protein to be produced," says William Guggino, Ph.D., director of Hopkins' Gene Therapy Center. "But laboratory and animal studies indicate it is capable of doing so."

For the Hopkins study, 12 adults with mild forms of cystic fibrosis are scheduled to participate in a year long trial. Because patients will enter the study one at a time, results are not expected before early 1997. Only if the treatment is found effective and safe for use in adults will it be tried in children, say researchers.

To make the gene transport system, the researchers insert normal copies of the CFTR gene into the virus. Using a tiny plastic tube and fiberoptic bronchoscopy, the virus is dripped into the nose and a lobe of the right lung. The virus is expected to enter the nucleus of epithelial cells and direct the DNA to make copies of its passenger, the normal CFTR gene. If it works, a missing protein -- one needed to move salt and water across cells -- is made. As a result, thin, fluid mucus is produced in the lungs. A defective CFTR gene results in thick, dry mucus that builds up, contributing to repeated infections and inflammation that destroy lung tissue and shorten life span.

Cellular changes in the nose will be calculated with a technique called transepithelial potential difference measurement, which determines the small electrical voltage created by the movement of salt and water across mucus membranes. Increased activity could mean that the gene therapy is having a positive effect, say researchers. Such measurements are not yet available for testing lung cells.

The AAV vector was developed by researchers at Hopkins and Targeted Genetics, a Seattle biotechnology firm. With funding from the Cystic Fibrosis Foundation and the National Institutes of Health, Flotte, Guggino and Targeted Genetics' Barrie Carter, Ph.D., led a team of researchers in studies that began soon after discovery of the cystic fibrosis gene (CFTR) in 1989. With help from Hopkins' Gene Therapy Center and Hopkins' Cystic Fibrosis Research Center, they learned important details about gene expression and the biological aspects of the vector.

Flotte received research funding from Targeted Genetics Corporation, which was used in the development of the AAV vector described in this press release. The Johns Hopkins University licensed the rights to the vector production process to Targeted Genetics in exchange for future royalties, which will be shared by the University, Flotte, Guggino and their laboratories. The terms of this arrangement have been reviewed and approved by the University in accordance with its conflict-of-interest policies.

-- JHMI --
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