Design and development of polymers for gene delivery

Key Points Human gene therapy utilizes genetic material – DNA or RNA – as a therapeutic for genetic, acquired and infectious diseases. Gene therapy's potential is great, but the lack of safe and efficient gene delivery methods is a limiting obstacle to clinical implementation. Gene delivery methods include recombinant viruses and synthetic materials such as lipids, polypeptides and polymers. Safety concerns limit the use of viral vectors. Non-viral gene delivery is typically much safer but suffers from generally unsatisfactory delivery efficiency. Gene delivery vectors should protect the genetic material from nucleolytic enzymes, provide potentially long lifetime in the blood, and direct delivery to a specific tissue or cells. Furthermore, the vector must provide a mechanism for entering the target cell, transiting the cytosol, crossing the nuclear membrane and releasing the genetic material at the appropriate point in this process. Non-viral vectors typically lack one or more of the necessary functions. The earliest synthetic vehicles reported in the literature are off-the-shelf materials, not originally designed for gene delivery. These include polylysine, polyethylenimine, and poly(amido amine) dendrimers. The gene delivery efficacy of such materials is serendipitous and, perhaps not surprisingly, typically insufficient for clinical application. In recent years, a variety of polymers have been designed specifically for gene delivery. Often, such polymers are designed to be non-toxic and to address particular steps in the gene delivery process, for example, escape from endocytic vesicles into the cytoplasm. While many of these materials are better than off-the-shelf polymers, their delivery efficiency remains several orders of magnitude below that of recombinant viruses. Based on the large number of studies of off-the-shelf and specifically designed gene delivery polymers, much has been learned about the structure-function relationships of polymer vectors. With growing understanding of polymer gene delivery mechanisms and continued efforts of creative and talented polymer chemists, it is likely that polymer-based gene delivery systems will become an important tool for human gene therapy. The lack of safe and efficient gene-delivery methods is a limiting obstacle to human gene therapy. Synthetic gene-delivery agents, although safer than recombinant viruses, generally do not possess the required efficacy. In recent years, a variety of effective polymers ha