NEW YORK (Reuters Health) - By “retargeting” an adenoviral vector, an international research team has developed a new gene therapy technique for treating metastasized melanoma that spares normal tissue. In vitro and in vivo studies have shown improved safety and efficiency of transduction over conventional adenoviral gene therapy.
Gene therapy for treatment of cancer has been plagued by insufficient gene transfer efficiency and by toxicity to normal tissues, Dr. David T. Curiel, at the University of Alabama at Birmingham, and his colleagues note in their report, published in the International Journal of Cancer for January 1.
To overcome these issues, the team ablated the native adenoviral tropism by blocking the virus’s ability to bind to integrins and to its primary receptor, coxsackie-adenovirus receptor (CAR). This double mutant virus exhibited a 230-fold relative decrease in transduction of normal cells compared with the wildtype vector.
They then made the vector tumor specific by inserting an antibody fragment directed to high molecular weight melanoma-associated antigen (HMWMAA), which is associated with melanoma development and progression. When applied to freshly purified CAR-negative primary melanoma cells, transduction was increased more than 50-fold compared with vector with wild-type virus, the report indicates.
“As best we can tell, [HMWMAA] is preserved with advanced disease states,” for which their modified vector was designed, Dr. Curiel, told Reuters Health.
“There have been some trials of similar CRAD (conditionally replicative adenoviruses) agents used systemically for prostate cancer,” that showed a good safety profile, he added.
His team has completed in vivo studies of local disease in mice, the researcher said, and is now extending this research to disseminated disease. “So far, our murine studies have shown we preserve the specificity we need, while retaining an excellent safety profile,” he said.
With National Cancer Institute support, he hopes to see human trials as early as 12 to 18 months from now.
“Disseminated melanoma has been a particularly difficult context, and we’re hopeful this new agent will provide a possible treatment modality,” Dr. Curiel concluded.
Source: Int J Cancer 2004;108:136-145. [ Google search on this article ]
MeSH Headings:Biological Therapy: Genetic Engineering: Genetic Techniques: Investigative Techniques: Therapeutics: Gene Therapy: Analytical, Diagnostic and Therapeutic Techniques and EquipmentCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
