Drugs Made of RNA: Development and Application of Engineered RNAs for Gene Therapy

I.      Drude; V.      Dombos; S.      Vauleon; S.      Muller

Abstract

During the past decade, RNA has become a focus of investigation into new therapeutic schemes: antisense RNA, interfering RNA and trans-cleaving ribozymes are used to silence undesired gene expression. As an additional option with its own therapeutic potential, ribozymes may be employed to specifically alter the sequence of RNA. Among these RNA based strategies the mode of action varies: while antisense and interfering RNAs are capable of making specific contacts to other RNA molecules with the result of employing the cellular machinery for degradation of the RNA target, trans-cleaving ribozymes fold into specific three-dimensional structures to form catalytic centres and to specifically cleave a chosen RNA target. Beyond this, trans-splicing ribozymes have been engineered to first cleave a RNA target followed by ligation of a new RNA fragment delivered with the ribozyme. The latter strategy potentially extends the application of ribozymes from inhibition of gene expression to RNA repair, i. e. correction of genetic disorders at the level of RNA, and has already shown promising results in cell culture experiments. On the other side, advances in RNA synthesis, ribozyme engineering, delivery methods and expression systems have greatly enhanced the prospects of ribozymes, antisense and interfering RNAs in gene therapy. This review provides an overview of existing strategies for potential RNA based gene therapy. It is focussed on the engineering of ribozymes and functional RNAs to be used as drugs and on the basic molecular principles of their action.

Keywords: Antisense oligonucleotide, gene therapy, RNA, RNA repair, ribozymes, siRNA

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