Introduction
Articles about mutations that cause genetic disorders frequently include a suggestion that gene therapy will likely provide a cure for the disease in the future. In fact, ongoing efforts to sequence the human genome, to understand the roles of genes during development, and to determine the molecular pathogenesis of disease will almost “naturally” lead to the use of nucleic acids for the treatment of diseases in the future.
Somatic gene therapy can be defined as the treatment of inherited or acquired diseases by the introduction and expression of genetic information in somatic cells. Genetic disorders that are caused by loss-of-function mutations might be treated by introducing a functional copy of the mutated gene into the appropriate tissue. Good candidate disorders for somatic gene therapy include the many inborn errors of metabolism, such as hemophilia A or B, which are caused by either a low amount or the complete absence of a single functional gene product. These disorders have been characterized at the DNA level, and the disease-causing mutations can be relatively easily identified in individual patients.
Many acquired diseases, such as different types of cancer, are less well-defined at the molecular level. However, because of their frequency and their impact on public health, interest in the development of gene therapy for these disorders is particularly high. In fact, most of the clinical gene therapy trials that have been conducted so far relate to the treatment of malignant tumors. Despite the many ongoing clinical trials, as yet, there have been no clear examples of the successful treatment of any human disease by gene transfer.
Possibly the single most important reason preventing a broad application of gene transfer in the treatment of diseases, whether inherited or acquired, is the lack of both safe and effective gene transfer technologies. What are the requirements for the use of a vector as a vehicle for gene transfer in patients with inborn errors of metabolism? The vector should efficiently transport and deliver foreign genes to different cell types, both in vitro and in vivo. Following gene transfer, these genes should be permanently expressed at physiological levels. In many cases, expression will need to be tissue-specific and regulated. The vector should be safe, stable, and easily manufactured to high yields.
While several nonviral and viral gene transfer vectors have been tested in different systems, currently, there is no vector system available that meets all of these requirements. With the realization that efficient delivery of genes into tissues is at the heart of successful somatic gene therapy, many research groups are concentrating their efforts on refining the different aspects of the multi-step process of gene transfer.
