title: Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7.
abstract: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by disruption of the survival motor neuron 1 (SMN1) gene, partly compensated for by the paralogous gene SMN2. Exon 7 inclusion is critical for full-length SMN protein production and occurs at a much lower frequency for SMN2 than for SMN1. Antisense oligonucleotide (ASO)-mediated blockade of an intron 7 splicing silencer was previously shown to promote inclusion of SMN2 exon 7 in SMA mouse models and mediate phenotypic rescue. However, downstream molecular consequences of this ASO therapy have not been defined. Here we characterize the gene-expression changes that occur in an induced model of SMA and show substantial rescue of those changes in central nervous system tissue upon intracerebroventricular administration of an ASO that promotes inclusion of exon 7, with earlier administration promoting greater rescue. This study offers a robust reference set of preclinical pharmacodynamic gene expression effects for comparison of other investigational therapies for SMA.
authors: Division of Genetics and Genomics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors: John F
authors: JF
authors: Staropoli
authors: Division of Genetics and Genomics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors: Huo
authors: H
authors: Li
authors: Neuroscience Drug Discovery, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors: Seung J
authors: SJ
authors: Chun
authors: Division of Genetics and Genomics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors: Norm
authors: N
authors: Allaire
authors: Neuroscience Drug Discovery, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors: Patrick
authors: P
authors: Cullen
authors: Division of Genetics and Genomics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors: Alice
authors: A
authors: Thai
authors: Division of Genetics and Genomics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors: Christina M
authors: CM
authors: Fleet
authors: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors: Yimin
authors: Y
authors: Hua
authors: Neuroscience Drug Discovery, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors: C Frank
authors: CF
authors: Bennett
authors: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors: Adrian R
authors: AR
authors: Krainer
authors: Division of Genetics and Genomics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors: Doug
authors: D
authors: Kerr
authors: Division of Genetics and Genomics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA.
authors: Alexander
authors: A
authors: McCampbell
authors: Neuroscience Drug Discovery, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors: Frank
authors: F
authors: Rigo
authors: Division of Genetics and Genomics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA. Electronic address: john.carulli@biogenidec.com.
authors: John P
authors: JP
authors: Carulli
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005091:Exons; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000187:drug effects / Q000235:genetics
chemical_list: D016376:Oligonucleotides, Antisense; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein
keywords: Antisense; Gene expression; Mouse model; Oligonucleotide; SMN2; Spinal muscular atrophy