Gene therapy is a promising drug delivery mechanism for the treatment of spinal disorders. Currently, the technique has been most useful in enhancing growth factor therapy for spinal fusion, intervertebral disc regeneration, and spinal cord injury healing. Gene therapy allows for the high-level local production of growth factors, obviating the need for slow release carriers or continuous infusion pumps that are otherwise necessary because of the short half-lives of most peptide growth factors. Although continuous expression is desirable, growth factor therapy is usually intended to be transient. The typical expression profile of Ad vectors--at a high level over 2 weeks or so--has been ideal, leading to its widespread use in these applications. Despite the ability of Ad to deliver genes directly in vivo, however, the cell-based ex vivo approach has been used widely in spinal applications. In spinal cord injury, cells such as peripheral nerve or Schwann cells may provide a permissive substrate for axonal growth [51]. For spinal fusion and IVD regeneration, ex vivo manipulation of cells facilitates gene transfer, because bone and IVD tissue are too dense to be penetrated by injection of Ad or other vectors. The use of cells may be advantageous in these applications in which new tissue formation is the goal. Finally, the use of genetically modified cells may decrease the inflammatory reaction induced by Ad vectors. Although gene therapy for spinal disorders has been centered around Ad-mediated transfer of single growth factor genes, the options for candidate genes and vectors are growing rapidly. Ad vectors are being improved by decreasing their immunogenicity and altering their tropism [2]. Vectors based on other viruses (such as herpes, adeno-associated virus, and lentivirus) are being developed, also with lower immunogenicity and with longer durations of expression [26,67]. Regulated expression, such as with the tetracycline regulated promoter, is being developed so that genes can be turned on or off as needed. Such regulation may be sensitive even to physiologic cues in the future [68,69]. Finally, the high throughput technologies, such as the gene chip, are elucidating thousands of genes that may be good candidates for the enhancement of bone healing and IVD and spinal cord regeneration. Genes whose products not only support bone, fibrocartilage, or axon growth but also neutralize natural inhibitors or promote tissue remodeling and maturation may be good future candidates. In the future, a series of vectors with multiple genes that are regulated by physiologic cues might be used to enhance spinal fusion, restore IVD tissue, or support spinal cord healing.
