title: The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy.
abstract: The neuromuscular disorder spinal muscular atrophy (SMA), the most common inherited killer of infants, is caused by insufficient expression of survival motor neuron (SMN) protein. SMA therapeutics development efforts have focused on identifying strategies to increase SMN expression. We identified a long non-coding RNA (lncRNA) that arises from the antisense strand of SMN, SMN-AS1, which is enriched in neurons and transcriptionally represses SMN expression by recruiting the epigenetic Polycomb repressive complex-2. Targeted degradation of SMN-AS1 with antisense oligonucleotides (ASOs) increases SMN expression in patient-derived cells, cultured neurons, and the mouse central nervous system. SMN-AS1 ASOs delivered together with SMN2 splice-switching oligonucleotides additively increase SMN expression and improve survival of severe SMA mice. This study is the first proof of concept that targeting a lncRNA to transcriptionally activate SMN2 can be combined with SMN2 splicing modification to ameliorate SMA and demonstrates the promise of combinatorial ASOs for the treatment of neurogenetic disorders.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Constantin
authors.initials: C
authors.lastname: d'Ydewalle
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Ramos
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Noah J
authors.initials: NJ
authors.lastname: Pyles
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Shi-Yan
authors.initials: SY
authors.lastname: Ng
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Gorz
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Pilato
authors.affiliation: Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Ling
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Lingling
authors.initials: L
authors.lastname: Kong
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Ward
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.affiliation: Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205, USA. Electronic address: csumner1@jhmi.edu.
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Sumner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012326:RNA Splicing; D016372:RNA, Antisense / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D016376:Oligonucleotides, Antisense; D016372:RNA, Antisense; D062085:RNA, Long Noncoding; C000597152:SMN2 protein, mouse; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: SMA therapeutics; SMN; antisense oligonucleotides; long non-coding RNA; spinal muscular atrophy