title: Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy.
abstract: Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system.
authors.affiliation: Genetic Resource Science, The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Laurent P
authors.initials: LP
authors.lastname: Bogdanik
authors.affiliation: Genetic Resource Science, The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Osborne
authors.affiliation: Genetic Resource Science, The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Crystal
authors.initials: C
authors.lastname: Davis
authors.affiliation: Genetic Resource Science, The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Whitney P
authors.initials: WP
authors.lastname: Martin
authors.affiliation: Genetic Resource Science, The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Andrew
authors.initials: A
authors.lastname: Austin
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: Genetic Resource Science, The Jackson Laboratory, Bar Harbor, ME 04609; cat.lutz@jax.org.
authors.forename: Cathleen M
authors.initials: CM
authors.lastname: Lutz
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000503:physiopathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010641:Phenotype
chemical_list: D016376:Oligonucleotides, Antisense
keywords: SMA; antisense oligonucleotide; motor unit number estimation; neuromuscular junction