Antisense Oligonucleotides as Therapeutic Agents—Is the Bullet Really Magical?

Abstract

Because of the specificity of Watson-Crick base pairing, attempts are now being made to use oligodeoxynucleotides (oligos) in the therapy of human disease. However, for a successful outcome, the oligo must meet at least six criteria: (i) the oligos can be synthesized easily and in bulk; (ii) the oligos must be stable in vivo; (iii) the oligos must be able to enter the target cell; (iv) the oligos must be retained by the target cell; (v) the oligos must be able to interact with their cellular targets; and (vi) the oligos should not interact in a non-sequence-specific manner with other macromolecules. Phosphorothioate oligos are examples of oligos that are being considered for clinical therapeutic trials and meet some, but not all, of these criteria. The potential use of phosphorothioate oligos as inhibitors of viral replication is highlighted.

Inhibition of renal cell carcinoma angiogenesis and growth by antisense oligonucleotides targeting vascular endothelial growth factor

“…In the present studies, we used a VEGF independent tumour model of RCC (VEGF-R negative) to evaluate the in vitro and in vivo efficacy of a different VEGF antisense PS-ODNs sequence (V515). Antisense oligodeoxynucleotide technology provides an approach for inhibiting gene expression with target specificity as a particular advantage (Stein and Cheng, 1993;Engelhard, 1998). Antisense oligonucleotides are easy to produce in large quantities which make them potentially more practical than antisense RNA vector delivery approaches.…”

Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity

“…This method of modifying the ODN structure has been employed by others to improve the efficacy of ODN therapies in diseases such as cancer, 18 but these techniques were not without problems and limitations. 19 Other studies using ODNs to control CNV, such as the aptamer Figure 6 Flow diagrams of the experimental design. Rats from group one (a) were used to establish the longevity and efficacy of the dendrimer plus ODN-1 conjugate in comparison to eyes injected with ODN-1 alone.…”

SupraMolecular BioVectors (SMBV) improve antisense inhibition of erbB-2 expression

“…A sensitivity to carriers that is dependent on the cell type is thus apparent. The non-sequence-specific effects of phosphorothioate antisense ODNs strongly restrict their possibilities for clinical trials (Stein and Cheng, 1993;Gura, 1995;Stein, 1995). In our previous work, it was demonstrated that incorporation into SMBVs increases the half-life time of phosphodiester ODNs 11-fold in cell growth medium (Berton et al, 1997).…”

“…The antisense inhibition of PI85ebB-2 in SK-Br-3 cells, a human mammary adenocarcinoma cell model overexpressing the transmembrane receptor, has thus necessitated the use of either native phosphodiester ODNs at a very high concentration (Colomer et al, 1994) or nuclease-resistant phosphorothioate ODNs, carried by commercialized cationic lipids or not (Bertram et al, 1994;Brysch et al, 1994;Vaughn et al, 1995). Because the evidence is becoming stronger for the non-sequencespecific effects of phosphorothioate ODN (Stein and Cheng, 1993;Gura, 1995;Stein, 1995), the development of ODN carriers would seem necessary to improve both the transport and the stability of native ODNs, while preserving their target specificity. Synthetic commercialized cationic lipids, such as DOTMA or DOTAP (Capaccioli et al, 1993;Dean and Mckay, 1994), or synthetic carriers such as nanoparticles (Schwab et al, 1994) are widely used because of their efficiency in enhancing antisense ODN uptake into cells and decreasing their degradation.…”