BIOPHYSICAL THEORY AND MODELING |
Molecular and cellular barriers limiting the effectiveness of antisense oligonucleotides
Charles M. Roth 1*
1 Rutgers University
* To whom correspondence should be addressed. E-mail: cmroth{at}rci.rutgers.edu.
Submitted on November 30, 2004
Revised on January 28, 2005
Accepted on 7 July 2005
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Abstract |
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Antisense oligonucleotides present a powerful means to inhibit expression of specific genes, but their effectiveness is limited by factors including cellular delivery, biochemical attack, and poor binding to target. We have developed a systems model of the processes required for an antisense oligonucleotide to enter, gain access to its target mRNA, and exert activity in a cell. The model accurately mimics observed trends in antisense effectiveness with the stability of the oligonucleotide backbone and with the affinity/kinetics of binding to the mRNA, including the time course of uptake and inhibition. By varying the model parameters within the physically realizable range, we note that the major molecular and cellular barriers to antisense effectiveness are intracellular trafficking, oligonucleotide-mRNA binding rate and nuclease degradation of oligonucleotides, with a weaker dependence on total cellular uptake than might be expected. Furthermore, the model may serve as a predictive tool to design and test strategies for the cellular use of antisense oligonucleotides. The use of integrated mathematical modeling can play a significant role in the development of antisense and related technologies.
Key Words:
gene expression, hybridization, mathematical modeling, oligonucleotide delivery
