Antisense therapeutic agents

The first antisense therapeutic agent to reach the market is fomivirsen (ISIS 2922) (19). Fomivirsen is a 21-mer phosphorothioate oligodeoxynucleotide (Fig. 8.5). It inhibits human cytomegalovirus (CMV), a ubiquitous herpesvirus that is the most common cause of viral retinitis in immunocompromised patients, especially those with FIIV infection. Cytomegalovirus infection is characterized by the progressive destruction of retinal cells and, if untreated, leads to retinal detachment and blindness. Even with treatment, some degree of visual loss occurs in nearly all patients with a diagnosis of CMV retinitis. It can affect one or both eyes. 

Fig. 8.5. Structure of fomivirsen, the first marketed antisense therapeutic agent. (Adapted from Field AK. Viral targets for antisense oligonucleotides a mini review. Antiviral Res 1998 37 67-81 with permission.)...

An effective therapeutic agent must also have the abiUty to reach its target sequence m vivo. BioavailabiUty requires that the antisense oligonucleotide be able to pass through the cell membrane, and that it have a low affinity for nontarget cellular compartments and, in animal systems, nontarget organs. 

The potential of the chemically modified nucleic acid molecules has been proven by in vitro studies however, the in vivo therapeutic applicability of these molecules seems to be unsatisfactory because of their possible toxic effects (largely unknown) and adverse bioavailability. In this view, both antisense and transfection technologies require reliable and efficient systems for their delivery into target cells. On the basis of this consideration, the development of an efficient nucleic acid delivery system represents one of the key steps for these therapeutic agents, which are necessary for a practical clinical utilization of natural or unnatural oligonucleotides. 

Oligonucleotide-based drugs such as antisense drugs, aptamers, and small interfering RNA (siRNA) have attracted considerable attention as promising therapeutic agents for the treatment of various human diseases [59], To develop... 

Antisense RNA. Novel Pharmacological and Therapeutic Agents, CRC Press, New York, 1997, pp. 131-148. 

Fomivirsen became the first approved therapeutic agent developed with antisense medical technology. 

An effective therapeutic agent must also have the ability to reach its target sequence in vivo. In order to enhance membrane transport, antisense oligonucleotides are frequently modified by covalent attachment of carrier molecules or lipophilic groups. 

Bunnell, B.A. and Morgan, R.A. (1997) Development of retroviral vectors expressing antisense RNA to inhibit replication of the human immunodeficiency virus. In B.Weiss (ed.) Antisense Oligodeoxynucleotides and Antisense RNA, Novel Pharmacological and Therapeutic Agent, CRC Press, Inc., Boca Raton, FL, pp. 197-212. 

Stein, C.A. and Cheng, Y.C. (1993) Antisense oligonucleotides as therapeutic agents—Is the bullet really magical Science, 261, 1004-1012. 

Nyce, J.W. 1997. Respirable antisense oligonucleotides as novel therapeutic agents for asthma and other pulmonary diseases. Expert Opin. Investig. Drugs 6 1149-1156. 

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