APPS November 2002 Meeting Abstract 2406


D. Martino, S. Fletcher, M. Grounds, S.D. Wilton, The Australian Neuromuscular Research Institute and the University of Western Australia.

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.

(1) Riquelme C, Larrain J, Schonherr E et al. Journal of Biological Chemistry. 2001;276:3589-3596.

(2) Mann CJ, Honeyman K, Cheng AJ et al. Proceedings of the National Academy of Sciences USA. 2001;98:42-47.

(3) Strauss M. Nature Medicine. 1998;4:274-275.

(4) Baker BF, Monia BP. Biochimica et Biophysica Acta 1999;1489:3-18.

(5) McPherron AC, Lawler AM, Lee SJ. Nature. 1997;387:83-90.

(6) Lee SJ, McPherron AC. Current Opinion in Genetic Development. 1999;9:604-607.

(7) Walder RY, Walder JA. Proceedings of the National Academy of Sciences USA 1988;85:5011-5015.

(8) Zamore PD, Tuschl T, Sharp PA et al. Cell. 2000;101:25-33.

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