Prediction of death in the SMNΔ7 mouse model of spinal muscular atrophy: insight into disease stage and progression.

ABSTRACT

Proximal Spinal Muscular Atrophy (SMA) is a debilitating neuromuscular disease and a leading inherited genetic cause of infant death. To date, there is no effective treatment for SMA. The SMNΔ7 neonatal mouse model of SMA recapitulates key features of the severe form of SMA and remains a valuable tool in preclinical drug discovery. At any particular postnatal age (P), the disease progression in the SMNΔ7 mouse model is not universal, as some animals die as early as the day of birth and others live for up to three weeks. Identification of the disease stage in SMNΔ7 mice, independent of age, would aid in the design and interpretation of preclinical studies. We developed a score (CD score), derived from body weight analysis, that allowed us to gain insight into the disease progression and predict death. Respiratory complication is a leading cause of mortality in the SMA patient and this phenotype has been reported in severe mouse models of SMA. We subsequently measured muscle and brain tissue lactate levels, an indirect measure of hypoxia, in SMNΔ7 mice at P10 and correlated these measures to respiratory rate. SMNΔ7 mice showed a significant increase in tissue lactate and a decrease in respiratory rate in comparison to control. The CD score correlates linearly with tissue lactate level and respiratory rate. The finding of lactate buildup in the SMNΔ7 mouse and the correlation with a score that is predictive of disease stage provide an interesting insight into the disease pathophysiology and a possible biomarker for SMA.