Antisense drugs are exogenous oligonucleotides that bind to specific endogenous nucleic acid sequences. Binding to mRNA prevents the construction of proteins by ribosomes and similarly, binding to specific gene sequences on DNA prevents both RNA coding and protein production. The application of antisense technology is broad, since this approach can be used to inhibit the production of a wide range of proteins, including stimulatory and inhibitory molecules.
While the synthesis of antisense molecules using modern combinatorial chemical approaches is easily automated, the delivery of these molecules to the appropriate intracellular and intranuclear sites is more difficult. The first antisense drug to be approved (ISIS Pharmaceutical Inc.) was for the treatment of cytomegalovirus retinitis in patients with AIDS. The route of administration of this drug is unique: direct intraocular injection. While this does deliver sufficient drug to the appropriate site, it illustrates well the ADME problems associated with antisense drugs.
To date, most regulatory authorities have treated antisense drugs in the much same way as any other biological product. The additional constraints that apply to gene therapies (for example) have not been imposed. Since these oligonucleo-tides have specific binding activities, safety considerations are usually dependent on the potential for non-specific effects of protein synthesis inhibition. At present, with the current limited experience, there would appear to be sound in vitro methods for the testing of the specificity of antisense drugs to be predictive for their tolerability in man. Furthermore, when the properties of the protein that is inhibited are discrete and consistent across individuals, then it is likely that the potential adverse effects will be predictable.
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