Development of Safer Gene Delivery Systems to Minimize the Risk of Insertional Mutagenesis-Related Malignancies: A Critical Issue for the Field of Gene Therapy
Integrating gene delivery systems allow for a more stable transgene expression in mammalian cells than the episomal ones. However, the integration of the shuttle vector within the cellular chromosomal DNA is associated with the risk of insertional mutagenesis, which, in turn, may cause malignant cell transformation. The use of a retroviral-derived vector system was responsible for the development of leukemia in five children, who participated in various clinical trials for the treatment of severe combined immunodeficiency (SCID-X1) in France and in the United Kingdom. Unfortunately, the hematological malignancy claimed the life of one patient in 2004, who was enrolled in the French clinical trial. In addition, adeno-associated-viral-(AAV-) mediated gene transfer induced tumors in animal models, whereas the Sleeping Beauty (SB) DNA transposon system was associated with insertional mutagenesis events in cell culture systems. On these grounds, it is necessary to develop safer gene delivery systems for the genetic manipulation of mammalian cells. This paper discusses the latest achievements that have been reported in the field of vector design. 1. Introduction Gene transfer technology requires the introduction of recombinant genetic elements into human cells and holds a considerable therapeutic potential for the treatment of a wide variety of pathological conditions, such as cancer, genetic disorders, neurological illnesses, diabetes, infectious diseases, and cardiovascular maladies [1–7]. The gene-based treatments both of cancer and infectious diseases may require only a transient expression of the recombinant genetic elements, which have the function to destroy either neoplastic tissues, or cells that harbor an infectious agent [3, 4]. Conversely, genetic disorders, neurological illnesses and cardiovascular maladies need a long-term transgene expression, as the treatment of these maladies envisions the introduction of functional copies of certain genes in the attempt to correct the phenotype of the disease [3, 4]. A long-term transgene expression is also required for autologous T lymphocytes that are genetically engineered to express recombinant T cell receptors, which may impart binding specificity either for neoplastic markers or infected cells [5–7]. To this end, gene delivery systems that integrate their genome into the target cell chromosomal DNA allow for a more stable and long-lasting transgene expression [3, 4]. Various types of gene delivery systems are currently available [3, 4, 8–16]. The most common gene transfer models derive from
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