Mouse models of SMA: tools for disease characterization and therapeutic development

Abstract

Mouse models of human disease are an important tool for studying disease mechanism and manifestation in a way that is physiologically relevant. Spinal muscular atrophy (SMA) is a neurodegenerative disease that is caused by deletion or mutation of the survival motor neuron gene (SMN1). The SMA disease is present in a spectrum of disease severities ranging from infant mortality, in the most severe cases, to minor motor impairment, in the mildest cases. The variability of disease severity inversely correlates with the copy number, and thus expression of a second, partially functional survival motor neuron gene, SMN2. Correspondingly, a plethora of mouse models has been developed to mimic these different types of SMA. These models express a range of SMN protein levels and extensively cover the severe and mild types of SMA, with neurological and physiological manifestation of disease supporting the relevance of these models. The SMA models provide a strong background for studying SMA and have already shown to be useful in pre-clinical therapeutic studies. The purpose of this review is to succinctly summarize the genetic and disease characteristic of the SMA mouse models and to highlight their use for therapeutic testing.

Pharmacology of a Central Nervous System Delivered 2′-O-Methoxyethyl–Modified Survival of Motor Neuron Splicing Oligonucleotide in Mice and Nonhuman Primates

“…These include small molecules to augment SMN2 transcription, correct SMN2 splicing, cause translational readthrough, and stabilize SMN2 transcripts (Lunn and Wang, 2008); SMN gene delivery to replace SMN protein (Foust et al, 2010;Passini et al, 2010); antisense oligonucleotide (ASO)-based approaches to correct SMN2 splicing (Lim and Hertel, 2001;Miyajima et al, 2002;Cartegni and Krainer, 2003;Skordis et al, 2003;Singh et al, 2006;Hua et al, 2007Hua et al, , 2008Hua et al, , 2011Dickson et al, 2008;Williams et al, 2009;Osman et al, 2012;Porensky et al, 2012;Mitrpant et al, 2013;Zhou et al, 2013); and antisense-producing vector-based strategies (Geib and Hertel, 2009;Meyer et al, 2009), including trans-splicing (Coady et al, 2007;Coady and Lorson, 2010). Some of these strategies have not yet been tested in animal models of SMA, but others have already been shown to be beneficial (Bebee et al, 2012).…”

Effect of genetic background on the phenotype of theSmn2B/-mouse model of spinal muscular atrophy

“…Several mouse models of SMA have been generated (reviewed in (22)). One common strategy is deleting the mouse Smn gene while introducing the human SMN2 gene (and/or its variants) into the mouse genome.…”

ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets

“…This null mutant, Smn −/− , served to highlight SMN as a developmentally essential protein since its complete ablation is embryonic lethal (Schrank et al, 1997) The heterozygous Smn +/− however, does not develop the typical histopathological SMA hallmarks and remains at best a hypomorphic model for the disease (Schrank et al, 1997; Bowerman et al, 2014). Thus, several alternate SMA models were eventually created in order to more closely mimic the human pathology by either introducing partially functional human SMN constructs onto the Smn −/− background or by rendering the endogenous murine Smn gene similar to the SMN2 copy (reviewed in Bebee et al, 2012). At present, the most commonly used SMA models are termed Smn −/− ; SMN2 (Hsieh-Li et al, 2000; Monani et al, 2000), Smn −/− ; SMN2 ; SMN Δ7/Δ7 (Le et al, 2005) and Smn 2 B /− mice (Hammond et al, 2010; Bowerman et al, 2012a) and range from severe (death within the first post-natal week) to intermediate phenotypes (average lifespan of 30 days).…”