Several promising therapeutic strategies for the treatment of Spinal Muscular Atrophy (SMA) are currently being pursued. As these therapies start to move from the research laboratory to the clinic, it becomes imperative to understand how effective these therapies will be after the onset of disease and if there is a critical window for drug delivery. To address this question of timing in delivering therapies, we have designed a study to evaluate the efficacy of increasing survival motor neuron (SMN) levels throughout development using a new preclinical SMA mouse model, called the Burgheron mouse. In this proposal we describe the Burgheron model, which we generated by breeding a combination of alleles to achieve mice that have intermediate SMN2 levels. Previous attempts to engineer mild SMA models have been relatively unsuccessful, resulting in mice with near normal life spans and little to no measurable phenotype. The Burgheron mice have a noted decrease in body weight, a mean lifespan of 54 days of age and quantifiable abnormalities at the neuromuscular junction, and measure differences in muscle strength. This increased lifespan presents a clear advantage over the currently used severe models of SMA that die early at 17 days of age in that it allows us to begin testing the effects of increasing SMN at later postnatal time points, even well past weaning. By incorporating a conditional inversion allele at the Smn1 locus we can transform the Burgheron model described above into an inducible system that activates SMN production via tamoxifen induction. This allows us to better characterize the effects of introducing SMN into a disease model at various time points in disease progression. In addition, we have chosen a number of different candidate therapeutics to serve the purpose of tool compounds to explore the question of a therapeutic window for treatment.
Spinal Muscular Atrophy (SMA) is a neurodegenerative disease and the number one genetic killer of infants and toddlers. This proposal describes a unique mouse model for mild SMA and the preclinical testing of a number of promising therapies administered at different time points of disease. This work will help identify the therapies that will likely be effective in treating SMA across a range of disease severity seen in patients, as well as to define a therapeutic window for which treatment will produce a benefit.