The Use Of Skeletal Muscle To Express Genes For The Treatment Of Cancer
- PDF / 294,489 Bytes
- 17 Pages / 468 x 720 pts Page_size
- 44 Downloads / 133 Views
THE USE OF SKELETAL MUSCLE TO EXPRESS GENES FOR THE TREATMENT OF CANCER Stephen Coe, Michael Harron, Marc Winslet, and Geoffrey Goldspink Department of Anatomy and Developmental Biology and Department of Surgery The Royal Free and University College Medical School University of London, UK., Royal Free Campus Rowland Hill St. London NW3 2PF
1. INTRODUCTION The available evidence shows that skeletal muscle is an appropriate target tissue for the transfer of DNA for the treatment of a number of diseases. These include those in which a systemic protein is absent or defective as well as muscle diseases per se such as Duchenne muscular dystrophy. It has also been shown that it is an appropriate target tissue for the introduction of vaccine DNA although the requirements for effective gene therapy procedures are somewhat opposite to those in which the main purpose is to elicit an immune response. This review deals with the design of gene constructs for the treatment of cancer including the vectors and the regulatory elements required for optimisation of expression following introduction of the relevant cDNA by intramuscular injection. The relative merits and problems associated with each type of vector including the immunogenic responses they elicit are discussed. The latter is relevant even when introducing vaccine genes as the immune response is required from the anti cancer cDNA not from other parts of the gene construct. Direct intramuscular injection of plasmid DNA was shown by Jon Wolff’s group (Wolff et al., 1990) to result in a small percentage of the fibres taking up and expressing the cDNA. This expression has been shown to persist for a considerable time (Wolff et al., 1992). Levels of expression were improved by using different regulatory sequences to drive the expression of the introduced cDNA (Hansen et al., 1991; Novo et al., 1995; Skarli et al., 1998) and by introducing the plasmid constructs into young muscle (Wells and Goldspink, 1992). Plasmids are very useful for transfecting muscle by intramuscular injection. However, the possibilities of using other vectors are discussed. Hence this Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
95
96
S. Coe et al.
review also deals with the immune response to the vectors as well as the gene product of the introduced cDNA as this is one of the crucial issues in gene therapy.
2. DESIGN OF VECTORS AND GENE CONSTRUCTS FOR APPROPRIATE EXPRESSION IN MUSCLE In any gene therapy protocol one needs to consider the construction of the gene cDNA or genomic DNA to be transferred, the vector backbone, as well as host factors in determining immune responses. Consideration needs to be given to individual components as any one of them can influence the therapeutic efficacy of a gene therapy approach. In this review these factors will be discussed. However, it is clear that additional factors such as the host immune status (Michou et al., 1997), dose of vector (Svenson et al., 1997), and mode of d
Data Loading...
