title: SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice.
abstract: Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: James
authors.initials: J
authors.lastname: Palacino
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Susanne E
authors.initials: SE
authors.lastname: Swalley
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Song
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Atwood K
authors.initials: AK
authors.lastname: Cheung
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Shu
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Mailin
authors.initials: M
authors.lastname: Van Hoosear
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Youngah
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Donovan N
authors.initials: DN
authors.lastname: Chin
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Basel, Switzerland.
authors.forename: Caroline Gubser
authors.initials: CG
authors.lastname: Keller
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Beibel
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Renaud
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Smith
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Salcius
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Shi
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Hild
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Servais
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Monish
authors.initials: M
authors.lastname: Jain
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Deng
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bullock
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: McLellan
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Schuierer
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Murphy
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Basel, Switzerland.
authors.forename: Marcel J J
authors.initials: MJ
authors.lastname: Blommers
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Cecile
authors.initials: C
authors.lastname: Blaustein
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Frada
authors.initials: F
authors.lastname: Berenshteyn
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lacoste
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Thomas
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Basel, Switzerland.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Roma
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Michaud
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Tseng
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Porter
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Vic E
authors.initials: VE
authors.lastname: Myer
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Tallarico
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Curtis
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Fishman
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Dietrich
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Dales
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Sivasankaran
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis; D012322:RNA Precursors / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D016019:Survival Analysis; D055540:Survival of Motor Neuron 2 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D012322:RNA Precursors; D012330:RNA, Double-Stranded; D017412:Ribonucleoprotein, U1 Small Nuclear; C000597152:SMN2 protein, mouse; D054852:Small Molecule Libraries; C490687:Snrnp70 protein, mouse; D055540:Survival of Motor Neuron 2 Protein