Pam Barber, Children's Hospital of Columbus, 614-722-4598, [email protected]Amy Nance, Children's Hospital of Columbus, 614-722-4592, [email protected]
For Release April 29, 2001
CHILDREN'S RESEARCH INSTITUTE OF COLUMBUS RELEASES
STUDY FINDINGS ON THE DEVELOPMENT OF RECEPTOR-TARGETED
ADENO-ASSOCIATED VIRUS (AAV)VECTORS
FOR THE TREATMENT OF CYSTIC FIBROSIS Researchers Find Solution for Enhancing Efforts to Replace Defective Cystic Fibrosis Genes with Normal Genes
BALTIMORE, APRIL 29, 2001 -- In ongoing clinical studies, researchers are working on ways to replace defective cystic fibrosis genes with normal genes. Previous studies have identified challenges to using viral vectors as a delivery system. However, a new study reveals the strategies that have been developed to physically modify adeno-associated virus (AAV) vectors to permit efficient targeted gene delivery to airway epithelium. Researcher Jeffrey S. Bartlett, Ph.D., of the Children's Research Institute, located on the campus of Columbus Children's Hospital, presented the findings Sunday, April 29 at the 2001 Pediatric Academic Societies' annual meeting.
Previous studies have shown that the primary factor limiting AAV infection of airway epithelium is the absence of heparan sulfate proteoglycan (HSPG), the cellular receptor for AAV, on these cells. Like other viruses, AAV must first bind to a specific receptor on the surface of a cell before it can enter the cell and deliver its genetic payload. Dr. Bartlett's laboratory has recently defined the process through which AAV attaches to and enters target cells. In this study, his team has modified normal AAV vectors by introducing "key" sequences into the virus shell that allow vectors to attach to and enter airway cells that display a corresponding "lock." This has allowed infection to proceed independent of the normal HSPG-dependent entry pathway. Paramount to the success of this approach was an extensive computer-assisted analysis of structural relatedness between AAV and other viruses for which three-dimensional structures have been determined.
"We have now pinpointed, using physical and biological criteria, which sites within the AAV capsid are amenable to the insertion of targeting epitopes," explained Dr. Bartlett. "Our study shows that vector-mediated gene delivery can be targeted and occur independent of HSPG-binding. Hence, we have developed a novel targeted gene transfer system, which will have significant impact not only on cystic fibrosis gene therapy, but on many gene therapy paradigms."
In simple terms, gene therapy involves the replacement of a gene that does not function properly with a normal copy of that same gene so that normal function can be restored. AAV is a non-pathogenic (non-disease causing) virus that has been used in studies to "carry" or deliver normal copies of cystic fibrosis genes to the lungs of patients with cystic fibrosis lung disease. Cystic fibrosis is the most common inherited genetic disease in the Caucasian population, occurring once in every 2,000 live births. Patients with cystic fibrosis are born with cystic fibrosis genes that do not work properly.
Recombinant AAV is an appealing vector system for cystic fibrosis gene therapy. In fact, clinical trials have been conducted using this vector system for the treatment of cystic fibrosis. However, these trials have been less than successful. In 2000, Dr. Bartlett presented study findings that identified reasons AAV may have certain inherent limitations in regard to the ability to transfer and express genes in the lung. This new study suggests an approach to solving this issue and should ultimately increase the effectiveness of AAV vector-mediated cystic fibrosis gene transfer.
"In the laboratory, we have solved the challenges limiting the effectiveness of AAV-mediated gene transfer to the airway epithelium," added Dr. Bartlett. "The next step will be to test this approach in the clinical setting."
Columbus Children's Hospital ranks among the top 10 in NIH research awards and grants to freestanding children's hospitals in the country. With nearly 500,000 patient visits each year, Children's Hospital is a 107-year-old pediatric healthcare network treating newborns through age 21. In 2000, the Children's Research Institute conducted more than 90 research projects. Pediatric Clinical Trials International (PCTI), a site management organization affiliated with the hospital, also coordinated 43 clinical trials. In addition to having one of the largest ambulatory programs in the country, Children's offers specialty programs and services, including more than 18 support groups. Each year, more than 75,000 consumers receive health and wellness education and 2,500 students from 50 institutions and 500 residents receive training at Children's. More information on Children's Hospital of Columbus is available by calling (614) 722-KIDS (5437) or through the hospital's Web site at http://www.childrenscolumbus.org.
RSS