Antisense therapy for angioplasty restenosis. Some critical considerations.

Abstract

The high affinity of even relatively short sequences of DNA for their target mRNA suggests that antisense agents represent an ideal method of suppressing specific gene products both in vitro and in vivo. In experiments performed thus far, an effect on the target mRNA in cultured vascular cells and in the vessel wall can be documented. The in vitro activity, toxicity, and pharmacokinetic data of antisense oligonucleotides are encouraging, and the in vivo animal experiments demonstrating suppression of neointimal formation are very promising. If animals trials presently under way show continued suppression not only of intimal formation but also of loss of lumen caliber after a single application, then effective delivery of antisense oligonucleotides is a realistic possibility. Nevertheless, some words of caution regarding the use of antisense oligonucleotides are warranted. Potential nonspecific effects of antisense oligonucleotides should be carefully considered in studies in which antisense agents are used to define biological functions of specific genes. In particular, demonstration that the target mRNA has been suppressed does not prove that other sequences within the mRNA pool have not also been suppressed. Critical control measures include adding back the target mRNA or protein and demonstrating similar biological effects with antisense sequences, which also suppress target gene expression directed at different regions of the target mRNA. At the clinical level, the systemic effects of antisense oligonucleotides, the dosage required, the timing of administration compared with mechanical intervention, and the toxicity of breakdown products all need to be established. In addition, the most appropriate targets for antisense use in restenosis remain largely obscure. Indiscriminate suppression of cell-cycle genes or proto-oncogenes may be as acutely toxic as current anticancer chemotherapy if the site delivery is not completely localized. Furthermore, much of the clinical evidence suggests that restenosis is a chronic process, continuing to develop weeks to months after the procedure. If this is the case, then the current approaches that rely on a transient, local application of an antisense agent may fail. If, however, a target gene is identified that is specific to vascular tissue, then repeated administration of an antisense agent may be tolerated via a systemic route. This approach has proved successful in targeting mutated genes with little suppression of closely related genes and with minimal systemic toxicity. An alternative approach is to transfect the target tissue with a gene that makes it susceptible to systemic delivery of a drug that is not normally toxic to mammalian cells.(ABSTRACT TRUNCATED AT 400 WORDS)