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UID:20251217T134631EST-6223jmurp3@132.216.98.100
DTSTAMP:20251217T184631Z
DESCRIPTION:Dr. Adrian Krainer\nProfessor\nCold Spring Harbor Laboratory\n“
 Correction of SMN2 RNA Splicing as a Therapeutic Strategy for\nSpinal Musc
 ular Atrophy”\n \nSpinal Muscular Atrophy (SMA) is a genetic disease chara
 cterized\nby progressive degeneration of motor neurons in the anterior hor
 n\nof the spinal cord\, which in turn leads to severe muscle weakness\nand
  atrophy. SMA is caused by deletion or loss-of-function\nmutations in the 
 Survival-of-motor-neuron (SMN1) gene. The\nparalogous SMN2 gene\, present 
 in one or more copies in all SMA\npatients\, attenuates the severity of SM
 A\, but expresses only a low\nlevel of full-length SMN protein\, due to al
 ternative splicing that\nresults in inefficient inclusion of exon 7. Incre
 asing the extent\nof SMN2 exon 7 inclusion to express more full-length\, f
 unctional\nSMN protein in motor neurons is a promising approach to treat S
 MA.\nWe have been using antisense oligonucleotides to identify and\ntarget
  splicing silencer elements\, so as to block the action of\nsplicing repre
 ssors and thereby increase the efficiency of exon 7\ninclusion. I will des
 cribe how we are delivering these antisense\noligonucleotides to the CNS o
 f SMA mouse models carrying a human\nSMN2 transgene\, so as to achieve spl
 icing correction in spinal-cord\nmotor neurons. This mechanism-based appro
 ach has yielded a\npromising drug candidate for SMA therapy.\n \nReference
 s:\n \nCartegni L\, Krainer AR (2002) Disruption of an SF2/ASF-dependent\n
 exonic splicing enhancer in SMN2 causes spinal muscular atrophy in\nthe ab
 sence of SMN1. Nature Genet 30: 377-384.\nCartegni L\, Hastings ML\, Calar
 co JA\, de Stanchina E\, Krainer AR\n(2006) Determinants of exon 7 splicin
 g in the spinal muscular\natrophy genes\, SMN1 and SMN2. Amer J Hum Genet 
 78: 63-77.\nHua Y\, Vickers TA\, Baker BF\, Bennett CF\, Krainer AR (2007)
 \nEnhancement of SMN2 exon 7 inclusion by antisense oligonucleotides\ntarg
 eting the exon. PLoS Biol 5: e73.\nHua Y\, Vickers TA\, Okunola HL\, Benne
 tt CF\, Krainer AR (2008)\nAntisense masking of an hnRNP A1/A2 intronic sp
 licing silencer\ncorrects SMN2 splicing in transgenic mice. Amer J Hum Gen
 et 82:\n834-848.\nPrior TW\, Krainer AR\, Hua Y\, Swoboda KJ\, Snyder PC\,
  Bridgeman\nSJ\, Burghes AH\, Kissel JT (2009) A positive modifier of spin
 al\nmuscular atrophy in the SMN2 gene. Amer J Hum Genet 85:\n408-413.\nHas
 tings ML\, Berniac J\, Liu YH\, Abato P\, Jodelka FM\, Barthel L\,\nKumar 
 S\, Dudley C\, Nelson M\, Larson K\, Edmonds J\, Bowser T\, Draper\nM\, Hi
 ggins P\, Krainer AR (2009) Tetracyclines that promote SMN2\nexon 7 splici
 ng as therapeutics for spinal muscular atrophy.\nScience Transl Med 1: 5ra
 12.\n \n
DTSTART:20100611T160000Z
DTEND:20100611T160000Z
LOCATION:McIntyre Medical Building\, CA\, QC\, Montreal\, H3G 1Y6\, 3655 pr
 omenade Sir William Osler
SUMMARY:Biochemistry Seminar Dr. Adrian Krainer
URL:/channels/event/biochemistry-seminar-dr-adrian-kra
 iner-163798
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