APPS November 2002 Meeting Abstract 2406

Antisense nucleic acids function on the basis of Watson-Crick hybridisation with a target sequence and induce changes in the flow of information from gene sequence to protein. There are various outcomes from these interactions, depending upon the mechanism through which a particular antisense molecule induces its effect. These may include the targeted degradation of RNA products¹, redirection of natural splicing mechanisms², the induced correction of genomic mutations (gene correction)³ or the inhibition of translational events⁴. We have investigated three different mechanisms of antisense action and compared their ability to induce transient suppression of the products of the myostatin gene. This gene is known to be a negative regulator of muscle growth⁵ that inhibits myoblast proliferation⁶ and may potentially be a relevant target gene with which to investigate antisense effects in muscle. In this study we compare three different antisense strategies that are known to invoke fundamentally different mechanisms. These are: 1) the phosphorothioate deoxyoligoribonucleotides (PS-ODN) known to activate the ubiquitous RNAseH enzyme and induce targeted destruction of DNA-RNA hybrid molecules⁷ 2) the 2'-O-methyl oligoribonucleotides (2OMeAO) that redirect nuclear splicing events to exclude exons from the mRNA transcript 3) A dsRNA molecule with a 2'ACE chemistry that is reported to induce a potent silencing pathway in plants and mammalian systems⁸. Transient suppression of the myostatin product could increase muscle growth resulting from hyperplasia and/or hypertrophy and this may hold potential as a treatment for patients with muscle wasting conditions.