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.

Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy

“…In this study, we also explored the potential clinical benefit of myostatin inhibition on mice treated with lower doses of AON, aimed at mimicking the situation of patients with the chronic forms of SMA II and III and those who may be under insufficient SMN‐restoring drug treatment. Encouraging results have recently presented that myostatin inhibition exerts therapeutic effect in SMA mice with less severe phenotypes: in particular, inhibition of myostatin using intramuscular injection of AAV1‐follistatin or monoclonal antibody ameliorates muscle atrophy in the Δ7 SMA mice dosed with low, sub‐optimal doses of an SMN2 splicing modifier small molecule . Intraperitoneal administration of AAV mediated a soluble form of the ActRIIB extracellular domain, by blocking the activin receptor, and also elicited great improvement in muscle mass and force in the mild SMA C/C mouse model .…”

Emerging therapies and challenges in spinal muscular atrophy

“…Encouragingly, recent results from models of milder SMA phenotypes suggest that some therapeutic efficacy may be possible even at late disease stages. 75 Although the therapeutic window for SMA types III and IV has not been defined, the normal early motor development may suggest that it is linked to age of presentation and broader than types I and II. Preliminary clinical trial data are emerging and indicating that with SMN repletion motor neurons may not be irreversibly doomed.…”

Time Is Motor Neuron: Therapeutic Window and Its Correlation with Pathogenetic Mechanisms in Spinal Muscular Atrophy

“…Another recent study succeeded in obtaining a milder SMA phenotype through administration of a suboptimal dose of SMN2 splicing modifier in a Δ7 mouse model [27]. These mice survived longer (reaching adult age) than untreated mice and showed adult SMA-like pathology, i.e., synaptic defects in NMJs and muscle atrophy.…”