title: Pharmacologically induced mouse model of adult spinal muscular atrophy to evaluate effectiveness of therapeutics after disease onset.
abstract: Spinal muscular atrophy (SMA) is a genetic disease characterized by atrophy of muscle and loss of spinal motor neurons. SMA is caused by deletion or mutation of the survival motor neuron 1 (SMN1) gene, and the nearly identical SMN2 gene fails to generate adequate levels of functional SMN protein due to a splicing defect. Currently, several therapeutics targeted to increase SMN protein are in clinical trials. An outstanding issue in the field is whether initiating treatment in symptomatic older patients would confer a therapeutic benefit, an important consideration as the majority of patients with milder forms of SMA are diagnosed at an older age. An SMA mouse model that recapitulates the disease phenotype observed in adolescent and adult SMA patients is needed to address this important question. We demonstrate here that Δ7 mice, a model of severe SMA, treated with a suboptimal dose of an SMN2 splicing modifier show increased SMN protein, survive into adulthood and display SMA disease-relevant pathologies. Increasing the dose of the splicing modifier after the disease symptoms are apparent further mitigates SMA histopathological features in suboptimally dosed adult Δ7 mice. In addition, inhibiting myostatin using intramuscular injection of AAV1-follistatin ameliorates muscle atrophy in suboptimally dosed Δ7 mice. Taken together, we have developed a new murine model of symptomatic SMA in adolescents and adult mice that is induced pharmacologically from a more severe model and demonstrated efficacy of both SMN2 splicing modifiers and a myostatin inhibitor in mice at later disease stages.
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089-2520, 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 90089-2520, USA.
authors.forename: Karen K Y
authors.initials: KK
authors.lastname: Ling
authors.affiliation: PTC Therapeutics, Inc., 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 90089-2520, USA.
authors.forename: Chunyi
authors.initials: C
authors.lastname: Zhou
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Karp
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: Nikolai
authors.initials: N
authors.lastname: Naryshkin
authors.affiliation: F. Hoffmann-La Roche Ltd, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland and.
authors.forename: Hasane
authors.initials: H
authors.lastname: Ratni
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 Ltd, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland and.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Metzger
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: PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Weetall
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089-2520, USA, mweetall@ptcbio.com cko@usc.edu.
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Ko
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000818:Animals; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D038681:Follistatin / Q000494:pharmacology*; D017353:Gene Deletion; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055435:Myostatin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012326:RNA Splicing / Q000187:drug effects*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D038681:Follistatin; D007155:Immunologic Factors; C525912:Mstn protein, mouse; D055435:Myostatin; C000597152:SMN2 protein, mouse; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein