Clinical trials using non-viral gene delivery systems

Abstract

Many clinical trials of gene and antisense therapies are currently underway. The percentage of gene therapy clinical trials for cancer diseases, monogenetic diseases, vascular diseases, infectious diseases, other diseases, and gene marking in healthy volunteers is 66% (n = 656), 9.4% (n = 93), 8.1% (n = 80), 6.6% (n = 65), 2.9% (n = 29), and 5.3% (n = 52), 1.2% (n = 12), respectively (Gene Therapy Clinical Trials Worldwide 2004).Approximately 38% of all cancer gene therapy trials use various forms of immune-modulatory agents, e.g., cytokines (24%, n = 241) and antigens (14%, n = 136), administered either systemically or locally.Twelve percent of the trials use tumor suppressor, and 7.5% suicide gene therapy. Further approaches, such as the insertion of multidrug resistance genes in stem cells, represent ∼5.7% (n = 56). The vast majority of gene therapy clinical trials are in phase I and only a very few have progressed to phase II. The phases of gene therapy clinical trials are as follows: phase I, 63%; phase I/II, 21%; phase II, 13%; phase II/III, 1.1%; and phase III, 1.7%. The majority of these studies have demonstrated that gene therapy is generally feasible using either viral or non-viral strategies. Vectors used in gene therapy clinical trials include retrovirus, adenovirus, naked/plasmid DNA, lipofection, herpes simplex virus, adeno-associated virus, accounting for 27% (n = 263), 26% (n = 258), 15% (n = 150), 8.6% (n = 85), 3% (n = 30), and 2.5% (n = 25), respectively. Cationic polymers have only been used in animal models and have not advanced into clinical trials due to various problems. While cancer gene therapy has not fulfilled the high expectations, remarkable efforts have been made to optimize gene delivery systems in vitro and in vivo by variously modifying the features of the vectors. However, additional research to elucidate the factors influencing opsonization, reticuloendothelial system (RES) uptake, and other forms of elimination in vivo is necessary.