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Bringing hope to life.™
DNA, RNA, and Protein Basics
In living organisms, DN A car r ies 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, doublestranded 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. In 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 diseasecausing proteins, antisense therapies focus on preventing the production of disease-causing proteins. Antisense drugs are based on small DNAlike or RNA-like constructs that bind to the proteincoding 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.
A nti s en s e th er ap y b lo ck s th e tr ansl ation 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
In November 2001, OncoGenex established a codevelopment relationship with Isis Pharmaceuticals for the development of OGX-011, the lead product in the OncoGenex pipeline. OGX-011 is a secondgeneration 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, OGX011 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. In March 2005, OncoGenex and Isis 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.
to 10-fold over first-generation chemistry and increased affinity to target mRNA. The first antisense constructs studied were based on the natural backbone structure of DNA. These constructs had an extremely high affinity for their t ar get s e quence s . second-generation chemistry with gapmer design significantly slows degradation of the drugs by protecting the drug from destructive nucleases. Because RNA hybridizes more tightly to RN A than to DN A . “0” generAtion PHoSPHoDiESTER (P=o) “1st ” generAtion PHoSPHoRoTHioATE (P=S) “2 nd” generAtion 2’MoE (MoDifiED P=S) CHARACTERiSTiCS: (1) Highly unstable to nucleases (2) Good affinity to target mRNA CHARACTERiSTiCS: (1) Better stability to nucleases but still degrades (2) Decreased affinity to target mRNA CHARACTERiSTiCS: (1) Best stability to nucleases (2) Increased affinity to target mRNA RESulT: (1) Rapidly degrades (2) Never advances to human trials RESulT: (1) Unknown tissue concentration (2) Unknown target regulation (3) Daily dosing RESulT: (1) Confirmed tissue concentration (2) Confirmed target regulation (3) Once a week dosing . Additionally. which increased the construct’s stability and made the technology more amenable to therapeutic use. President and CEO OncoGenex Technologies Inc. scientists attempted to alter the backbone of the antisense molecules. second-generation drugs are more active at lower doses. that promise has not yet been fully realized. With increased potency. First-generation drugs have demanded daily.736. and the modified DNA backbone decreased the affinity of the antisense molecule to its target mRNA sequence. However. s tr uc t ur e s b a s e d on naturally occurring DNA are subject to swif t degradation by nucleases and proved to be unsuitable for therapeutic uses. BC. In an ef for t to make antisense technology more amenable to therapeutic use.™ www. However. A further improvement incor por ates both fir st-gener ation and secondgeneration chemistries into “gapmers”: antisense sequences that have their ends modified with 2’MOE chemistr y while retaining at their centers firstgeneration chemistry. and in the future may allow for oral delivery. The improved affinity of second-generation drugs is primarily attributable to their design and composition. while first-generation drugs are entirely DNA-like. Second-generation drugs are composed of both RNAlike and DNA-like nucleotides. greater potency. Ho w e v er. and their lower specificity for their target mRNA keeps them from being as potent as is desirable. these constructs still had plasma half lives of only hours. adding the 2’MOE (2’-methoxyethyl) modification to the oligonucelotide backbone.ca Evolution of Antisense Technology The first researchers who worked on antisense technology saw the possibilities of new methods of drug design. The 2’MOE modified ends protect the construct from degradation. while the first generation center permits enzymatic degradation of the mRNA /antisense complex. The first successful backbone chemistry modified the phosphodiester structure in the DNA backbone to a phosphorothioate structure. the secondgeneration drugs have a greater affinity for their RNA targets and. a useful feature for long-term use given added patient convenience. Vancouver. The resulting slower clearance from the body allows for less frequent dosing. therefore. To increase the stability of the antisense compound. 400-1001 West Broadway. New developments in the chemistry of antisense give further hope to developing potent. giving significantly improved half life and binding affinity. Canada V6H 4B1 Telephone: 604.cOnTAcT infOrmATiOn ™ Scott D. Gapmer secondgeneration chemistry drugs have increased half-lives of 5. a second-gener ation chemistr y w as developed. Cormack. long-lasting antisense ther apies that are more conveniently adminstered. intravenous dosing.3687 Bringing hope to life.736.oncogenex.3678 | Fax: 604.
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