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Due to the lack of natural occurring plasmids in higher eukaryotes, most vectors currently used for the modification of mammalian cells and organisms are based on modified viruses. But the use of these virus-based vectors still has severe safety risks and therefore considerable efforts are made to design alternative vector systems, whose function are based on chromosomal elements and which behave as an autonomous unit in the cell. The construction of episomal vectors was hindered by our limited knowledge of the epigenetic regulation of replication in higher eukaryotes.

However, in the late 1990, a prototype non-viral episomal vector was constructed which replicates autonomously in all mammalian cells and is mitotically stable in the absence of selection. Its function relies on an expression unit linked to a scaffold/matrix-attached region (S/MAR). In this short review, we describe the rational of its construction and functioning. The prototype vector was improved within the past years with respect to establishment and expression efficiency and has now been tested for various preclinical applications. Eventually, S/MAR-based vectors will be improved to such a stage that they can provide a safe alternative to viral vectors to be used in gene therapy.

Gene therapy is a treatment for inborn and acquired diseases, although the development of safe and effective gene delivery system is a great challenge to make a gene therapy a success. Viral vectors have been used in a majority of clinics because of their high transfection efficiency in vitro and in vivo. However, their use has been limited because of several drawbacks, such as induction of immune response, recombination of wild-type viruses, limitation in the size of inserted gene, and difficulty in large-scale production. Nonviral vectors have been widely proposed safe alternatives to viral vectors because they have low immunogenicity, flexibility in the size of gene to be delivered, cell targetibility, and easy scalability of production, although they have low transfection efficiency compared to viral vectors. Among nonviral vectors, polyethylenimine (PEI) has been widely used as a standard gene carriers due to its high pH-buffering capacity for endosomal escape although high-molecular-weight PEI is too toxic owing to non-degradability. Recently, many types of degradable PEI have been studied due to high transfection efficiency with lower cytotoxicity. This review explains recent progress on the development of degradable PEIs as nonviral vectors. The present paper summarizes the transfection efficiency of DNA or silencing efficiency of small interfering RNA (siRNA) based on the kinds of degradable linkage between low PEI and crosslinkers. Degradable linkages, such as ester, disulfide, imines, carbamate, amide and ketal in the degradable PEIs are covered.