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Over the past 15 years substantial theoretical and applied efforts have been devoted to developing gene therapy for genetic disorders. For many diseases replacement of defective genes may provide an excellent therapeutic
approach. However, gene therapy as a general system for treatment of a variety of disorders is a work-in-progress and a future-directed technology. Here, I will review the general conceptual bases for gene therapy for the
treatment of a variety of genetic disorders.
Gene therapy can be divided into two fundamental approaches: germ-line and somatic gene therapy. Germ-line gene therapy has the specific aim of adding genes to cells that lead to reproduction and as a consequence result in
generational passage of the inserted genes. The overall concept of germ-line gene therapy is to modify the human gene pool and change the genetic structure of populations rather than individuals. Thus, germ-line
gene therapy is not in the realm of traditional medicine, since it is directed to “improving”: or “altering” the gene pool of large populations. Clearly, this approach has substantial ethical concerns due to the potential
for selecting genes to be modified. At the present time, this form of gene therapy is banned in civilized countries even though the technology is available to accomplish this in non-human animal systems.
In comparison, somatic gene therapy is directed to adding genes to non-reproductive cells so that cellular function can be altered in an individual. The overall concept is to change an abnormal cell function by adding
additional or new genes to those cells. This would lead to “permanent correction” of the cell type. Initially, the emphasis of somatic gene therapy was on disorders involving single gene abnormalities, i.e.,
Rubinstein Taybi Syndrome, or inborn errors of metabolism. The overall concept is to benignly insert genes into the human genome to achieve an appropriate level of function of a gene and to provide delivery of these genes
to specific cells or cell types that are fundamentally involved by the disease process. The hope would be to achieve permanent correction or cure of the disease.
In its simplest form somatic gene therapy would be directed to correct the disease genetic change in a single cell type that derives from a common origin. As an example, particular inherited diseases arise from
abnormalities of bone marrow cells, termed stem cells. These stem cells produce all of the blood cells [red and white blood cells and platelets] and can be distributed to the body. Some of these circulating cells
reside in tissues and become important residents of these organs. For example, macrophages are large cells involved in the recycling of compounds within the body. They derive from bone marrow stem cells. These
macrophages are the “sites” of pathology, or primarily involved cells, in many disorders. Thus, if genes could be targeted directly to the bone marrow stem cells, the defects in macrophages could be corrected. This
is the “target site of pathology hypothesis” in which the genetic change precursor cells can be altered and, hence, all derivative cells are altered leading to decreases in disease manifestations in the body.
To deliver genes to the target site of pathology, the “zip codes” that specify recognition by precursor cells must be understood. These “zip codes” are the recognition codes for receptors on cells that are specific for
given cell types. Because different viruses have specificity for particular cell types (i.e., hepatitis for the liver, adenovirus for the pulmonary system, rabies for the central nervous system), these organisms have developed
recognition signals on their surface for receptors on these cell types. Thus, different viruses attack different cell types due to their ability to recognize and enter selected cells: This is termed tropism.
The challenge to the “gene therapist” is to develop ways to remove the disease causing potential of viruses and use these defective viruses as packets to deliver genes to the target sites of pathology in various diseases.
Removal of disease causing genes of viruses is possible as is removal of genes that are involved in the reproduction of the viruses. Such “defective” viruses can be used to deliver any gene to the cells of interest in a
particular disease. Once the virus delivers the gene to the cells of interest the gene must express a production that will lead to correction or amelioration of specific disease manifestations. A major issue in gene
therapy has been the need for cellular division for viruses to be taken up into cells of the body and deliver the included genes. Consequently, organs in which the cells are not dividing present major problems both
experimentally and conceptually for gene therapy.
With specific reference to Rubinstein Taybi Syndrome, the central nervous system is a primary target for gene therapeutic approaches. However, the central nervous system are, in general, not dividing. Also, central
nervous system cells cannot be lost in large numbers since they are important to our daily functioning. Candidate viruses for the delivery of genes to the central nervous systems are relatively poorly understood and their
mode oead/control within the central nervous system is even less well understood. Since most inherited central nervous system diseases are globla in nature, i.e., they involve many different cell types within the brain
and any delivery system for genes to the brain would need to be global. This means that many of the cells within the brain would need to have the genes delivered to themand, then, expressed. Thus, fundamental
knowledge of how CNS viruses function and how they spread within the nervous system is esse3ntial to progress in the area of gene therapy for central nervous system diseases.
Given the above limiations and restrictions on gene therapy, there remain substantial research efforts concentrated in this area to develop effective gene therapy approaches for the treatment of many disorers. Over the
past 10 years enormous progress has been made in understanding gene function, gene expression, viral tropism and viral delivery systems for gene therapy. Thus, gene therapy remains a future technology that will require
substantial resource investment for the development of viable systems prior to incorporation into modern medicine. It is quite clear from the progress in the past decade, particularly in the area of localized cancers,
that gene therapy will become an integral part of medicine early in the 21st century.
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