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DNA resembles a ladder, forming a twisted, double-stranded structure. One strand of the ladder (sense) matches exactly with its complementary strand (antisense) antisense drugs are based on small DNA-like or RNA-like constructs.
DNA resembles a ladder, forming a twisted, double-stranded structure. One strand of the ladder (sense) matches exactly with its complementary strand (antisense) antisense drugs are based on small DNA-like or RNA-like constructs.
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DNA resembles a ladder, forming a twisted, double-stranded structure. One strand of the ladder (sense) matches exactly with its complementary strand (antisense) antisense drugs are based on small DNA-like or RNA-like constructs.
Copyright:
Attribution Non-Commercial (BY-NC)
Formati disponibili
Scarica in formato DOC, PDF, TXT o leggi online su Scribd
n living organisms, DNA carries all of the instructions for building the proteins that make up an organism, coded in small sections called genes. DNA consists of a constant backbone made of sugar and phosphate molecules as well as variable nucleotides or bases (Adenine, Thymine, Guanine, Cytosine, commonly known as A, T, G and C). DNA resembles a ladder, forming a twisted, double-stranded structure with the nucleotides making up the rungs of the ladder and the backbone forming the sides of the ladder. One strand of the ladder (sense) matches exactly with its complementary strand (antisense); the nucleotides that make up the rungs of the ladder are very specific in how they match each other. A always partners with T and C always partners with G. The sequence or order of these nucleotides establishes the cell's recipe for making proteins. n a process called transcription, DNA is used as a template to manufacture an RNA molecule, called messenger RNA (mRNA). mRNA communicates the genetic message found in DNA to other areas of the cell so protein production can occur. Like DNA, RNA is made up of nucleotide base pairs and a sugar-phosphate backbone. During translation phase, mRNA travels to the ribosome, which is the cell's machinery that assembles proteins based on the instructions contained in the mRNA. How Antisense Works While traditional drug therapies are based on designing compounds that block or inhibit disease-causing proteins, antisense therapies focus on preventing the production of disease-causing proteins. Antisense drugs are based on small DNA-like or RNA-like constructs that bind to the protein-coding strand of genetic message (mRNA), blocking the translation of the disease-causing protein. By binding to mRNA, antisense drugs prevent the genetic code from being read by the ribosome, which is responsible for translating and manufacturing proteins; additionally, the bound antisense/mRNA complex is enzymatically degraded so the protein cannot be synthesized. Antisense therapy blocks the translation phase of protein synthesis by binding to the specific genetic segment of mRNA that codes for production of a specific disease-causing protein. OGX-011 binds to the segment of mRNA that codes for clusterin. The OncOGenex AnTisense sTOry n November 2001, OncoGenex established a co-development relationship with sis Pharmaceuticals for the development of OGX-011, the lead product in the OncoGenex pipeline. OGX-011 is a second-generation antisense compound designed to knock out clusterin, a cell survival protein that is usually expressed in tumor cells in response to standard anti-cancer therapies. By inhibiting clusterin, OGX-011 sensitizes resistant tumors to conventional cancer therapeutics. Data from a Phase 1 clinical trial demonstrates that OGX-011 is well tolerated, achieves excellent drug concentration in target tissue, and inhibits the clusterin target in prostate cancer and lymph nodes. OGX-011 inhibited clusterin expression in prostate cancer cells by greater than 90% and inhibited clusterin expression in lymph nodes by greater than 95%. OGX-011 is currently being evaluated in Phase 2 clinical trials in prostate, breast and non-small cell lung cancers. n March 2005, OncoGenex and sis expanded their antisense drug development collaboration to include additional second-generation antisense cancer drug candidates, including the second product candidate in the OncoGenex pipeline, OGX-427. OGX-427 is designed to inhibit production of Heat Shock Protein 27 (Hsp27), a target that has been associated with treatment resistance and prevention of cell death in various cancer cells. OGX-427 is slated to enter the clinic in early 2006.
Evolution of Antisense Technology The first researchers who worked on antisense technology saw the possibilities of new methods of drug design. However, that promise has not yet been fully realized. First-generation drugs have demanded daily, intravenous dosing, and their lower specificity for their target mRNA keeps them from being as potent as is desirable. New developments in the chemistry of antisense give further hope to developing potent, long-lasting antisense therapies that are more conveniently adminstered. The first antisense constructs studied were based on the natural backbone structure of DNA. These constructs had an extremely high affinity for their target sequences. However, structures based on naturally occurring DNA are subject to swift degradation by nucleases and proved to be unsuitable for therapeutic uses. n an effort to make antisense technology more amenable to therapeutic use, scientists attempted to alter the backbone of the antisense molecules. The first successful backbone chemistry modified the phosphodiester structure in the DNA backbone to a phosphorothioate structure, which increased the construct's stability and made the technology more amenable to therapeutic use. However, these constructs still had plasma half lives of only hours, and the modified DNA backbone decreased the affinity of the antisense molecule to its target mRNA sequence. To increase the stability of the antisense compound, a second-generation chemistry was developed, adding the 2'MOE (2'-methoxyethyl) modification to the oligonucelotide backbone. A further improvement incorporates both first-generation and second-generation chemistries into "gapmers: antisense sequences that have their ends modified with 2'MOE chemistry while retaining at their centers first-generation chemistry. The 2'MOE modified ends protect the construct from degradation, giving significantly improved half life and binding affinity, while the first generation center permits enzymatic degradation of the mRNA/antisense complex. Gapmer second-generation chemistry drugs have increased half-lives of 5- to 10-fold over first-generation chemistry and increased affinity to target mRNA. The improved affinity of second-generation drugs is primarily attributable to their design and composition. Second-generation drugs are composed of both RNA-like and DNA-like nucleotides, while first-generation drugs are entirely DNA-like. Because RNA hybridizes more tightly to RNA than to DNA, the second-generation drugs have a greater affinity for their RNA targets and, therefore, greater potency. With increased potency, second-generation drugs are more active at lower doses. Additionally, second-generation chemistry with gapmer design significantly slows degradation of the drugs by protecting the drug from destructive nucleases. The resulting slower clearance from the body allows for less frequent dosing, and in the future may allow for oral delivery, a useful feature for long-term use given added patient convenience.