In vivo electroporation for gene therapy

Development of successful plasmid DNA-based gene transfer protocols has been handicapped by the lack of efficient delivery methods. Several methods such as particle bombardment, liposomes, ultrasound, and hydrodynamic therapy have improved DNA delivery. In vivo EP has emerged as an effective tool for DNA delivery for a variety of applications. A critical aspect with respect to in vivo EP is proper selection of delivery parameters. For immunotherapy, multiple applications may be necessary. The length and location of expression should be controlled by proper selection of the EP parameters. Established protocols can be found in the literature. All parameters, including voltage (field strength) or current, pulse width, number, and frequency (pulses per second), as well as electrode configuration and the delivery site, should be evaluated for each application. With this in mind, it is important to realize that publications may not contain complete EP parameters. Encouragingly, there is a growing availability of equipment and electrodes that can be used for in vivo EP (Puc et al., 2004) that will facilitate the use of this delivery method. The initiation of clinical trials is the true indication of the advancement of in vivo EP for gene transfer. The first clinical study was initiated in late 2004 at the H. Lee Moffitt Cancer Center and Research Institute (Tampa, FL; http://www. moffitt.usf.edu/). This is a phase I dose escalation trial in patients with accessible subcutaneous metastases with melanoma. The primary objectives are to determine the toxicity and maximum tolerated dose of intralesionally electroporated plasmid encoding for the human IL-12 cDNAs. Other clinical trials have since commenced. Administration of a plasmid encoding IL-2 directly into melanoma lesions followed by electroporation is being tested (Vical, San Diego, CA; http://www.vical.com/). Trials of intramuscular EP delivery of vaccines for prostate cancer (University of Southampton, U.K.; http://www.som.soton. ac.uk/research/cancersciences/research_groups/gvg/default.htm) and for cancers expressing HER-2 and/or carcinoembryonic antigen (CEA) (Merck & Co., Whitehouse Station, NJ; http:// www.merck.com/mrl/clinical_trials/enrolling. html) have been initiated. While pre-clinical studies have demonstrated the utility of in vivo EP, the true potential of this delivery approach will not be known until the results from these and future clinical studies are reported. © Mary Ann Liebert, Inc.