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BioDrugs
Published in: BioDrugs 1/2004

01-01-2004 | Drug Development

A Multi-Model Approach to Nucleic Acid-Based Drug Development

Authors: Dr Isabelle Gautherot, Regís Sodoyer

Published in: BioDrugs | Issue 1/2004

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Abstract

With the advent of functional genomics and the shift of interest towards sequence-based therapeutics, the past decades have witnessed intense research efforts on nucleic acid-mediated gene regulation technologies. Today, RNA interference is emerging as a groundbreaking discovery, holding promise for development of genetic modulators of unprecedented potency.
Twenty-five years after the discovery of antisense RNA and ribozymes, gene control therapeutics are still facing developmental difficulties, with only one US FDA-approved antisense drug currently available in the clinic. Limited predictability of target site selection models is recognized as one major stumbling block that is shared by all of the so-called complementary technologies, slowing the progress towards a commercial product.
Currently employed in vitro systems for target site selection include RNAse H-based mapping, antisense oligonucleotide microarrays, and functional screening approaches using libraries of catalysts with randomized target-binding arms to identify optimal ribozyme/DNAzyme cleavage sites. Individually, each strategy has its drawbacks from a drug development perspective. Utilization of message-modulating sequences as therapeutic agents requires that their action on a given target transcript meets criteria of potency and selectivity in the natural physiological environment. In addition to sequence-dependent characteristics, other factors will influence annealing reactions and duplex stability, as well as nucleic acid-mediated catalysis. Parallel consideration of physiological selection systems thus appears essential for screening for nucleic acid compounds proposed for therapeutic applications. Cellular message-targeting studies face issues relating to efficient nucleic acid delivery and appropriate analysis of response. For reliability and simplicity, prokaryotic systems can provide a rapid and cost-effective means of studying message targeting under pseudo-cellular conditions, but such approaches also have limitations.
To streamline nucleic acid drug discovery, we propose a multi-model strategy integrating high-throughputadapted bacterial screening, followed by reporter-based and/or natural cellular models and potentially also in vitro assays for characterization of the most promising candidate sequences, before final in vivo testing.
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Metadata
Title
A Multi-Model Approach to Nucleic Acid-Based Drug Development
Authors
Dr Isabelle Gautherot
Regís Sodoyer
Publication date
01-01-2004
Publisher
Springer International Publishing
Published in
BioDrugs / Issue 1/2004
Print ISSN: 1173-8804
Electronic ISSN: 1179-190X
DOI
https://doi.org/10.2165/00063030-200418010-00004

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