The first genetic therapy trial involving the direct transfer ofmodified human genetic material into a human, announced thisweek by the University of Michigan Medical Center, is seen asoffering a potentially broad new avenue to treating disease.
University of Michigan Medical Center (UMMC) researchers onJune 4 treated a 67-year-old woman with metastatic melanomaby injecting genes into a cancerous skin tumor. The UMMC trialwas also the first genetic therapy using a non-viral vector --liposomes in this case -- to deliver the gene in the tumor site.
If successful, gene injection could lead to treatments that,unlike prior gene therapies, may not require extensivemodifications for individual patients. Prior human genetherapy trials have been patient-specific, involving extractionof a patient's own immune cells from tumors, which aremodified and then returned to the patient.
"This approach marks a beginning; we have begun to use DNAas a drug," Gary J. Nabel, principal researcher, said of the invivo gene therapy. Although still in a very early stage ofdevelopment, gene injections could play important roles intreating many diseases, he said.
"This is a pharmaceutical product, not a service," Robert Zaugg,director of new business development for Vical Inc. of SanDiego, said on Thursday. Vical holds patent rights connected tothe gene injection technology. With the potential to be usedeffectively without modification on a large number of patients,gene injections could ultimately be less expensive and morewidely used than previous genetic therapies.
"The biggest negative today is that the amount of protein youcan deliver (with gene injection) is very small," compared withother gene therapies, Zaugg said. UM's Nabel joined Vical'sscientific board of advisers last fall, although neither he nor UMhas any other formal ties yet to the company, Zaugg said.
The objective of the initial UMMC gene injection trial involving12 patients is to determine safety and effective dosages of thetreatment. Under the study's protocol, each of four groups ofthree patients will receive a different dosage of the geneticmaterial.
Patients in the study, who all have been diagnosed withmetastatic melanoma with cutaneous lesions and have beengiven less than one year to live, were chosen on the basis thatthey would not benefit from further standard treatment suchas surgery, chemotherapy or radiation, according to the UMMC.Metastatic melanoma, the deadliest of skin cancers, kills anestimated 6,700 Americans a year.
The treatment strategy is to trigger an immune response in thepatient that destroys the tumor. The key component injectedinto the tumor site is the gene for a transplantation antigen,HLA-B7. Transplantation antigens, which appear on cellsurfaces, signal the immune system that a foreign entity ispresent. They also differ among individuals, which is the basisfor the body's rejection of transplanted organs.
Overcoming the transplantation barrier is key to developingthe gene therapies that don't need to be modified toindividuals, said Vical's Zaugg.
Liposomes are mixed in to enhance delivery of the HLA-B7 tothe tumor site, where it prompts the immune system torecognize all cells bearing HLA-B7 as foreign. In addition, thetreatment stimulates the immune system to recognize otherunmodified tumor cells and attack them.
If data proves promising, the next step would likely be toundertake an expanded study of perhaps 100 to 200 patientsto start assessing the treatment's efficacy, which could bemeasured by remission of the cancer in patients, Zaugg said.
Vical shares patent rights with the University of Wisconsin,which provided initial data from a Vical-funded research thatwas pursued by company researchers.
"Our goal is to be the experts in the application of thistechnology," Zaugg said. Vical is sure of its proprietary positionin the use of naked vectors. "Whatever Gary does willeventually come back to us," Zaugg said.
Privately held Vical is pursuing no near-term commercialprojects, but rather is now exploring the technology's potential,Zaugg said. However, it has a collaboration with Merck to applyits gene injection technology for anti-viral treatments.
Nabel, an associate professor of internal medicine and biologicalchemistry at UMMC, was a research fellow with DavidBaltimore at the Whitehead Institute of the MassachusettsInstitute of Technology in the mid-1980s, where he developedan interest in how genes activate the human immunodeficiencyvirus inside cells.
His approach to treating advanced skin cancer grew out of hisefforts to develop a unique system to delivery therapeuticgenes.
Companies involved in developing gene therapy include: GeneTherapy Inc. of Beltsville, Md., CytoTherapy Inc. of Providence,R.I., TargeTech Inc. of Meridien, Conn., and Somanetics of Troy,Mich.
-- Steve Payne and Ray Potter BioWorld Staff
(c) 1997 American Health Consultants. All rights reserved.