韩国裸舞

Dr. Adrian Krainer
Professor
Cold Spring Harbor Laboratory

鈥淐orrection of SMN2 RNA Splicing as a Therapeutic Strategy for Spinal Muscular Atrophy鈥�

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Spinal Muscular Atrophy (SMA) is a genetic disease characterized by progressive degeneration of motor neurons in the anterior horn of the spinal cord, which in turn leads to severe muscle weakness and atrophy. SMA is caused by deletion or loss-of-function mutations in the Survival-of-motor-neuron (SMN1) gene. The paralogous SMN2 gene, present in one or more copies in all SMA patients, attenuates the severity of SMA, but expresses only a low level of full-length SMN protein, due to alternative splicing that results in inefficient inclusion of exon 7. Increasing the extent of SMN2 exon 7 inclusion to express more full-length, functional SMN protein in motor neurons is a promising approach to treat SMA. We have been using antisense oligonucleotides to identify and target splicing silencer elements, so as to block the action of splicing repressors and thereby increase the efficiency of exon 7 inclusion. I will describe how we are delivering these antisense oligonucleotides to the CNS of SMA mouse models carrying a human SMN2 transgene, so as to achieve splicing correction in spinal-cord motor neurons. This mechanism-based approach has yielded a promising drug candidate for SMA therapy.

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References:

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Cartegni L, Krainer AR (2002) Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nature Genet 30: 377-384.

Cartegni L, Hastings ML, Calarco JA, de Stanchina E, Krainer AR (2006) Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. Amer J Hum Genet 78: 63-77.

Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR (2007) Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol 5: e73.

Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR (2008) Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Amer J Hum Genet 82: 834-848.

Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, Bridgeman SJ, Burghes AH, Kissel JT (2009) A positive modifier of spinal muscular atrophy in the SMN2 gene. Amer J Hum Genet 85: 408-413.

Hastings ML, Berniac J, Liu YH, Abato P, Jodelka FM, Barthel L, Kumar S, Dudley C, Nelson M, Larson K, Edmonds J, Bowser T, Draper M, Higgins P, Krainer AR (2009) Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy. Science Transl Med 1: 5ra12.

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