Viral, nonviral, and physical methods for gene delivery

Gene transfer is an emerging therapeutic modality for a wide spectrum of diseases. Its clinical adoption is, however, limited by the lack of safe and efficient gene delivery methods. Three classes of methods are currently under evaluation. The first class consists of genetically modified viruses, which include retroviruses, adenoviruses, adeno-associated viruses, and several others. These vectors are relatively efficient. However, their clinical application is associated with significant safety concerns, such as oncogenesis and acute inflammatory response. The second class is nonviral vectors, which are composed of synthetic components. These include complexes of DNA with lipids, polymers, or their combination. Many nonviral vector formulations, which incorporate functional components to facilitate nuclease protection, cellular/tissue targeting, endosomal release, and nuclear localization, have been investigated, mostly in vitro. These efforts have resulted in incremental advances in gene transfer efficiency, requiring further improvements for clinical applications. The third class of methods is based on the use of physical energy or force. Examples are gene gun, electroporation, and magnetofection. These methods are suitable for locoregional gene delivery. In this chapter, we will provide an overview of the state-of-the-art gene transfer methods, their strengths and weaknesses, and challenges and opportunities in this critical area of research, which will, to a large extent, determine the future prospect of gene therapy in the clinic.