Toxicologic Properties of 2-O-Methoxyethyl Chimeric Antisense Inhibitors in Animals and Man
Antisense inhibitors continue to mature as integral research tools for understanding biological mechanisms, and have made great progress as therapeutic agents since the last comprehensive reviews in this area were published . Of course, therapeutic applications are the ultimate goal for the technology, requiring a solid understanding of the molecular mechanisms, pharmacologic activity (both in vitro and in vivo), pharmacokinetic properties, toxicology, and clinical efficacy in specific disease areas. There are now numerous examples of pharmacologic activity in animal models, illustrating the ability of these inhibitors to regulate the expression of the targeted genes in vivo [2-4]. Evidence of antisense activity in patients has also been demonstrated for several targets in preliminary clinical trials [5-9], and more examples will likely follow. One pivotal area of therapeutic development where questions remain is toxicology. This is particularly the case in the context of clinical indications that have expanded beyond cancer therapy, and now include treatments for more chronic and non-life-threatening diseases, such as diabetes and cardiovascular disease. These latter indications obviously require a very thorough examination of the safety and tolerability profiles. This review will update the current state of knowledge surrounding the toxicologic assessment of these inhibitors. Much of the basics about this technology, both with regard to the toxicology, and specific mechanisms of action, have previously been reviewed and will not be repeated here .