title: Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is caused by the loss or mutation of both copies of the survival motor neuron 1 (SMN1) gene. The related SMN2 gene is retained, but due to alternative splicing of exon 7, produces insufficient levels of the SMN protein. Here, we systematically characterize the pharmacokinetic and pharmacodynamics properties of the SMN splicing modifier SMN-C1. SMN-C1 is a low-molecular weight compound that promotes the inclusion of exon 7 and increases production of SMN protein in human cells and in two transgenic mouse models of SMA. Furthermore, increases in SMN protein levels in peripheral blood mononuclear cells and skin correlate with those in the central nervous system (CNS), indicating that a change of these levels in blood or skin can be used as a non-invasive surrogate to monitor increases of SMN protein levels in the CNS. Consistent with restored SMN function, SMN-C1 treatment increases the levels of spliceosomal and U7 small-nuclear RNAs and corrects RNA processing defects induced by SMN deficiency in the spinal cord of SMNΔ7 SMA mice. A 100% or greater increase in SMN protein in the CNS of SMNΔ7 SMA mice robustly improves the phenotype. Importantly, a ∼50% increase in SMN leads to long-term survival, but the SMA phenotype is only partially corrected, indicating that certain SMA disease manifestations may respond to treatment at lower doses. Overall, we provide important insights for the translation of pre-clinical data to the clinic and further therapeutic development of this series of molecules for SMA treatment.
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Biological Sciences, Section of Neurobiology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Biological Sciences, Section of Neurobiology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Karen K Y
authors.initials: KK
authors.lastname: Ling
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Mollin
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Sheedy
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Yeh
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Petruska
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Narasimhan
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Amal
authors.initials: A
authors.lastname: Dakka
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Welch
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Karp
authors.affiliation: SMA Foundation, 888 Seventh Avenue, Suite 400, New York, NY 10019, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Chen
authors.affiliation: F. Hoffmann-La Roche, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel 4070, Switzerland.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Metzger
authors.affiliation: F. Hoffmann-La Roche, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel 4070, Switzerland.
authors.forename: Hasane
authors.initials: H
authors.lastname: Ratni
authors.affiliation: Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA and.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lotti
authors.affiliation: Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Tisdale
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Naryshkin
authors.affiliation: Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA and.
authors.forename: Livio
authors.initials: L
authors.lastname: Pellizzoni
authors.affiliation: SMA Foundation, 888 Seventh Avenue, Suite 400, New York, NY 10019, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Paushkin
authors.affiliation: Department of Biological Sciences, Section of Neurobiology, University of Southern California, Los Angeles, CA 90089, USA, mweetall@ptcbio.com cko@usc.edu.
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Ko
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA, mweetall@ptcbio.com cko@usc.edu.
authors.forename: Marla
authors.initials: M
authors.lastname: Weetall
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005091:Exons / Q000235:genetics; D006801:Humans; D049934:Isocoumarins / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage*; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D012867:Skin / Q000378:metabolism; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055540:Survival of Motor Neuron 2 Protein / Q000097:blood / Q000235:genetics*
chemical_list: D049934:Isocoumarins; D010879:Piperazines; C000621363:SMN-C1 compound; C000597152:SMN2 protein, mouse; D054852:Small Molecule Libraries; D055540:Survival of Motor Neuron 2 Protein