Abstract
The roots of gene therapy go back to the 1960s. One basic concept that emerged was the replacement of a defective gene with exogenous DNA representing the intact sequence. The notion that gene expression can be modified through the use of exogenous nucleic acids largely derives from studies that in 1977 first used single stranded DNA to inhibit the translation of a complementary RNA in a cell free system. In the following year, it was shown that a 13-mer DNA oligodeoxynucleotide, which was antisense to the Rous sarcoma virus, could inhibit viral reduplication in culture. In the 1980s, gene therapy was conceptualized. In 1980, Martin Cline attempted to correct an inherited metabolic defect in children by transfecting and re-infusing bone marrow cells. The study had not received prior permission and was unsuccessful. Cline lost his university chair at the University of California, Los Angeles and much of his NIH (National Institute of Health) funding. The molecular biology and clinical medicine communities working on gene therapy came together effectively for the first time at the Banbury Conference Center, Cold Spring Harbor Laboratories in 1983. The first approved gene therapy in the United States was undertaken in 1990 to correct an inherited enzyme deficiency.
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Notes
- 1.
Locked nucleic acids (LNAs) are high-affinity RNA analogs, in which the ribose ring is locked in a favorable conformation for Watson-Crick binding. They contain a methylene bridge linking the 2’ oxygen and 4’ carbon of the ribose sugar ring, thereby increasing their stability and decreasing their degradation. Locking also results in high stability after hybridization with a complementary DNA or RNA strand. Locked nucleic acid oligonucleotides typically consist of a mixture of locked and conventional bases. This allows optimization of their sensitivity and specificity.
- 2.
Phosphorodiamidate morpholino oligomers are neutrally charged antisense agents, wherein the deoxyribose moiety of DNA is replaced with a 6-membered morpholine ring and the charged phosphodiester inter-nucleoside linkage is replaced with phosphorodiamidate linkages. These agents are steric blockers that inhibit gene expression by preventing components of the splicing or translational machinery from binding. The neutral character avoids the binding to other cellular and extra-cellular proteins that can occur with charged oligonucleotide chemistries.
- 3.
ICP34.5 enables HSV-1 to reduplicate in neurons of the brain and spinal cord by conditioning post-mitotic cells for viral reduplication.
- 4.
Directed enzyme prodrug therapies use enzymes that are artificially introduced into the body to convert prodrugs to their active forms in the desired location within the body. Such strategies aim at reducing the systemic toxicity of a drug by achieving high levels of the active form only at the desired site. Due to the lack of specificity y many anti-cancer chemotherapy agents, directed enzyme prodrug therapies have been studied particularly for their use in cancer treatment. Specific strategies include antibody-directed, gene-directed, virus-directed, polymer-directed, and clostridia-directed enzyme prodrug therapies.
- 5.
Since 1999, gene therapy of X-SCID has restored the immune systems of children with the disorder. In 2002, two patients developed T-cell leukemia in a French trial of X-SCID, a 3rd child followed. The leukemias were caused after a retrovirus carrying a gene called γc (common γ chain) inserted into the oncogene lmo2 in bone marrow cells in infants less than 3 months old. Retroviruses tend to insert into active genes, perhaps because the condensed DNA containing chromatin opens up in these regions.
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Weber, G. (2015). Gene Therapy. In: Molecular Therapies of Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-13278-5_8
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