Quantitative antisense dose-response relationships: Mathematical modeling of antisense action under steady-state conditions

A quantitative theoretical analysis of antisense action is presented in which hyperbolic relationships between the logarithm of antisense oligodeoxynucleotide (AODN) ligand concentration, versus cognate messenger RNA (mRNA) and protein concentrations, are derived under conditions of steady state, This analysis incorporates a dual-compartment kinetic model of gene expression, The antisense dose-response functions yield an apparent equilibrium dissociation constant K-d (with the dimensions of concentration), which provides an index of binding affinity and AODN efficacy, Increases in K-d produce a parallel right shift in the theoretical dose-response curve, The dose ratio derived from the antisense concentrations that produce a 50 % reduction in phenotypical response, or mRNA/protein level (i,e., the ED(50)) for two agents of differing efficacy, is shown to equal the K-d ratio for the respective agents, The parameter K-d provides a potentially useful and experimentally quantifiable constant for comparing AODN analog efficacy, Application of quantitative antisense dose-response relationships (QADRRs) and K-d should provide a more rigorous foundation for the experimental evaluation of antisense effects.