Oligonucleotide Therapeutics: A Step Forward - Oligonucleotides

Given these facts, one might ask why this work5 is worthy of comment. First, the study involves a reasonable number of patients, and important pharmacokinetic data, including correlation of response with Bcl-2 levels, are provided. Second, it is difficult to deny that antitumor effects are being observed in some of these patients, with very little toxicity. If even a proportion of the antitumor effect is mediated by antisense mechanisms, then the urge to improve on what was observed becomes very compelling. In the short term, this might become possible by more rational (ie, biologically aware) use of available compounds. In the case of Bcl-2, for example, it is known that even marked reductions in protein do not necessarily kill cells, but it does render them more susceptible to apoptosis-inducing agents.33,34 Accordingly, when used alone, the Bcl-2 antisense oligonucleotide might well be expected to generate the type of clinical results reported in this article. The compound could prove much more potent when used in combination with low doses of available chemotherapeutic agents. Most cancer therapies consist of multiple agents, and it is likely that antisense compounds will prove no different. As noted by the authors, trials of this type are now ongoing and the results are eagerly awaited.
More basic challenges remain, and these must be addressed if this approach to specific antitumor therapy is to become a useful treatment approach. For example, a significant problem in this field is the limited ability to deliver oligonucleotides into cells and have them reach their target.35 As a general rule, oligonucleotides are taken up primarily through a combination of adsorptive and fluid-phase endocytosis.36 After internalization, confocal and electron microscopy studies have indicated that the bulk of the oligonucleotides enters the endosome/lysosome compartment, where most of the material either becomes trapped or degraded. Biologic inactivity is the predictable result of these events. Nevertheless, oligonucleotides can escape from the vesicles intact, enter the cytoplasm, and then diffuse into the nucleus, where they presumably acquire their mRNA or, in the case of decoys, protein target. The processes that regulate such trafficking and ultimately govern whether and where an oligonucleotide can interact with its target remain poorly understood and need elucidation.
Efficient delivery of antisense molecules will not solve all of the problems, however. For an oligonucleotide to hybridize with its mRNA target, it must find an accessible sequence. Sequence accessibility is at least in part a function of mRNA physical structure, which is dictated in turn by internal base composition and associated proteins in the living cell. Attempts to describe the in vivo structure of RNA, in contrast to DNA, have been fraught with difficulty. Accordingly, mRNA targeting is largely a random process, accounting for many experiments in which the addition of an oligonucleotide yields no effect on expression. Strategies to address this fundamental problem37,38 are presently under development.
Those of us who are actively engaged in the care of cancer patients are constantly reminded of the misery that aggressive anticancer therapy inflicts on the unfortunate individuals who must endure it. The importance of work designed to make such treatments more effective and less toxic cannot be overestimated. Investigators are following many paths toward this goal, including strategies designed to interrupt the most fundamental of processes within a cell, the expression of its genes. The article by Waters et al5 is a small but nonetheless important step on the road to accomplishing this goal. When finally achieved, as it surely will be, a giant leap for humankind will most definitely have been made.