(277b) Development of Virus/Polymer Chimeras As Gene Delivery Vectors

Human gene therapy holds the potential to revolutionize treatment of diseases ranging from cystic fibrosis to cardiovascular disease to cancer.  The primary bottleneck hindering the technology, however, is delivery of the therapeutic genetic material.  Recombinant viruses are highly efficient and are used in the majority of gene therapy clinical trials, but face serious safety concerns, are difficult to target to specific cells and tissues, and are expensive to produce.  Polymer-based vectors are generally safer, less expensive and more versatile, but lack the efficiency needed for clinical relevance.  The success of human gene therapy awaits development of safe and efficient methods for gene delivery.  We have recently pioneered a top-down approach to construction of novel vectors assembled from viral and synthetic components that are designed to exhibit advantages of both types of vectors.  Thus, we have prepared hybrid vectors through electrostatic complexation of retro- or lentivirus-like particles with polycations including polylysine, polyethylenimine and chitosan.  These hybrid vectors are internalized by cells via macropinocytosis, the polymer provides escape from macropinosomes into the cytosol, and the viral components provide highly efficient trafficking of their genetic cargo into the nucleus.  Further, targeting moieties may be conjugated to the polymer to provide cell-specific delivery.  This new class of vectors provides gene delivery efficiency similar to native viruses, provides genomic integration for sustained transgene expression, and is capable of transfecting quiescent cells.  Hybrid vectors, therefore, represent a new and promising approach for safe and efficiency gene delivery.