Transient suppression of the Myostatin gene transcript: A comparison of different antisense nucleic acid mechanisms
Martino, D., Fletcher, S., Grounds, M. and Wilton, S.D. (2003) Transient suppression of the Myostatin gene transcript: A comparison of different antisense nucleic acid mechanisms. In: 3rd Meeting of Australasian Gene Therapy Society, 30 April - 2 May 2003, Queensland Institute of Medical Research, Brisbane.
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 products, redirection of natural splicing mechanisms, the induced correction of genomic mutations (gene correction) or the inhibition of translational events. 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 product is known to be a negative regulator of muscle growth that inhibits myoblast proliferation and may potentially be a target 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 molecules 2) the 2’-O-methyl oligoribonucleotides (2OMeAO) that redirect nuclear splicing events to exclude exons from the mRNA transcript 3) A dsRNA molecule with 2’ACE chemistry that is reported to induce a potent silencing pathway in plant and mammalian systems. Transient suppression of the myostatin product could result in hyperplasia and/or hypertrophy of muscle and this may hold potential as a treatment for patients with muscle wasting conditions.
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