title: Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Naryshkin
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Weetall
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Amal
authors.initials: A
authors.lastname: Dakka
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Narasimhan
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Karen K Y
authors.initials: KK
authors.lastname: Ling
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Karp
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qi
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Woll
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Guangming
authors.initials: G
authors.lastname: Chen
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Nanjing
authors.initials: N
authors.lastname: Zhang
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Gabbeta
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Vazirani
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Bhattacharyya
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Bansri
authors.initials: B
authors.lastname: Furia
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Risher
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Sheedy
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Kong
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Ma
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Turpoff
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Chang-Sun
authors.initials: CS
authors.lastname: Lee
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Young-Choon
authors.initials: YC
authors.lastname: Moon
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Panayiota
authors.initials: P
authors.lastname: Trifillis
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Welch
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Colacino
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: John
authors.initials: J
authors.lastname: Babiak
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Neil G
authors.initials: NG
authors.lastname: Almstead
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA. friedrich.metzger@roche.com speltz@ptcbio.com.
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Peltz
authors.affiliation: SMA Foundation, 888 Seventh Avenue, Suite 400, New York, NY 10019, USA.
authors.forename: Loren A
authors.initials: LA
authors.lastname: Eng
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: Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Jesse L
authors.initials: JL
authors.lastname: Mull
authors.affiliation: Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Maureen S
authors.initials: MS
authors.lastname: Lynes
authors.affiliation: Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Paulo
authors.initials: P
authors.lastname: Fontoura
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Santarelli
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Haehnke
authors.affiliation: SMA Foundation, 888 Seventh Avenue, Suite 400, New York, NY 10019, USA.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: McCarthy
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmucki
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Ebeling
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Manaswini
authors.initials: M
authors.lastname: Sivaramakrishnan
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Ko
authors.affiliation: SMA Foundation, 888 Seventh Avenue, Suite 400, New York, NY 10019, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Paushkin
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Hasane
authors.initials: H
authors.lastname: Ratni
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Gerlach
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Anirvan
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland. friedrich.metzger@roche.com speltz@ptcbio.com.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Metzger
mesh_terms: D000284:Administration, Oral; D017398:Alternative Splicing / Q000187:drug effects*; D000818:Animals; D002478:Cells, Cultured; D003374:Coumarins / Q000008:administration & dosage* / Q000737:chemistry; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D049934:Isocoumarins / Q000008:administration & dosage* / Q000737:chemistry; D008136:Longevity / Q000187:drug effects*; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics; D017384:Sequence Deletion; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000737:chemistry; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D003374:Coumarins; D049934:Isocoumarins; D011744:Pyrimidinones; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D055540:Survival of Motor Neuron 2 Protein