Antisense mechanisms

A new antiviral agent, developed for treatment of CMV retinitis, can be administered by intravitreal injection. Formivirsen sodium is a phosphorothioate oligonucleotide that inhibits CMV replication through an antisense mechanism. It is formulated as a sterile and preservative-free solution and supplied in single-use vials (Vitravene ). The product is administered directly into the vitreous cavity posterior to the limbus through a 30-gauge needle. This procedure can be performed on an... 

The product inhibits replication of human CMV (HCMV) via an antisense mechanism. Its nucleotide sequence is complementary to a sequence in mRNA transcripts of the major immediate early region (IE2 region) of HCMV. These mRNAs code for several essential viral proteins and blocking their synthesis effectively inhibits viral replication. 

Antiselective poisoning, 5 258 Antisense agents, 77 626-627 Antisense compounds, 77 13-14 Antisense mechanism, 77 627 Antisense oligonucleotides, 77 627, 628 Antiseptics, 3 605, 606... 

Burgess TL, Fisher ER Ross SL, et al. The antiproliferative effect of c-myb and c-myc antisense oligonucleotides in smooth muscle cells is caused by a non antisense mechanism. Proc Natl Acad Sci USA I 995 92(9) 405l-4055. 

The second mechanism of hybridization-dependent toxicity is related to the reduction in expression of an unintended target by an antisense mechanism. 

An alternative to the inhibition of RNA metabolism by way of an antisense mechanism is to inhibit transcription by interacting with double-stranded DNA in chromatin. Of the two most obvious binding strategies for oligonucleotides binding to double-stranded nucleic acids, strand invasion and triple-strand formation, triple-stranding strategies, until recently, attracted essentially all of the attention. 

Phosphorothioate oligonucleotides have perhaps outperformed many expectations. They display attractive parenteral pharmacokinetic properties. They have produced potent systemic effects in a number of animal models and, in many experiments, the antisense mechanism has been directly demonstrated as the hoped-for selectivity. Further, these compounds appear to display satisfactory therapeutic indices for many indications. 

Vitravene (fomivirsen sodium, ISIS Pharmaceuticals see Table 9) remains the only antisense-based biopharmaceutical approved for general medical use (see also Part III, Chapter 3). The product is a 21-base phosphorothioate nucleotide that displays a base sequence complementary to certain human cytomegaloviral mRNA transcripts. Its administration inhibits viral replication through an antisense mechanism. Approved in the US in 1998 and in the EU in 1999, the product is indicated for the treatment of cytomegalovirus retinitis by intraocular injection in AIDS patients. It was withdrawn from the EU market in May 2002 for commercial reasons. 

These three drugs illustrate both the hope and the frustration that is experienced with this class of therapeutics. The antisense mechanism works in the cells, and protein synthesis can definitely be inhibited. Getting from cell culture observations to useful and effective therapies, however, is a long road, and several seemingly useful antisense agents have fallen by the wayside when tested in randomized, double-blind trials. Clearly, attention must be paid to getting the dosing sohedule, formulation, and route of administration optimized. 

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