La stratégie anti-sens : nouvelles approches thérapeutiques

Abstract

Selective control of gene expression can be achieved with nucleic acids which bind specific sequences of messenger RNAs. The so-called <<antisense>> strategy makes use of either synthetic oligonucleotides or RNA transcripts produced in situ from DNA constructs. Several mechanisms are involved in the inhibition of mRNA translation. The mRNA may be degraded by endogenous enzymes when it binds the antisense molecule. For instance, ribonuclease H (RNase H) cleaves the RNA in RNA-oligodeoxynucleotide hybrids. Oligonucleotides have been chemically modified to protect them against nuclease degradation and to enhance all uptake. Cell culture experiments have provided evidence for the sequence specificity of mRNA translation inhibition. Several animal experiments on tumors or viral infections have shown that antisense oligonucleotides can exert their inhibitory activity in vitro. A few clinical trials have been initiated in the fields of cancer and AIDS. Meanwhile basic research is continuing on the chemistry of modified oligonucleotides and on the development of carriers and vectors that could enhance the bioavailability and the pharmacokinetic behavior of antisense oligomers, together with their cell uptake and compartimentalization properties. Side effects due to oligonpuecleotide binding to other targets than nucleic acids have to be explored. DNA constructs expressing antisense RNA could be used in a gene therapy approach. A ribozyme structure can be incorporated in the RNA transcript to induce cleavage of the target messenger or viral RNA. Inhibition of growth factors such as IGF1 by antisense RNA has been shown to induce regression of glioblastoma in animal experiments. Antisense and ribozyme constructs have demonstrated inhibitory activity against HIV infection. Clinical trials will be initiated to evaluate the potential of these approaches in a cell therapy protocol. Antisense strategies offer new opportunities to control gene expression in a highly selective way. They have provided interesting tools in molecular and cellular biology to analyze the physiological role of specific genes. There are still many questions raised by the development of their therapeutic applications. The next few years should tell us what is the future of antisense approaches in both gene-specific pharmacology and gene therapy.