Proximal spinal muscular atrophy (SMA) is a neuro-degenerative disease that is a primary genetic cause of infant mortality. Deletion or mutation of the survival motor neuron-1 (SMN1) gene leads to the SMA disease in humans. The human genome harbors a nearly identical gene, SMN2, that is functionally redundant with SMN1. However, expression of the SMN2 gene is severely compromised as a result of a splicing mutation in exon 7. Disease severity in SMA patients is inversely correlated with the copy number of SMN2 with the lowest levels of SMN protein causing the most severe SMA phenotypes. While the severe forms of SMA are fatal, the intermediate and mild forms of the disease cause immobility and respiratory issues for patients. Restoration of SMN protein to severe SMA mouse models has shown partial rescue of the disease phenotype, however there has been no therapeutic testing for restoration of neurological defects in intermediate or mild models for SMA. Therefore, there is a critical need to develop an intermediate SMA mouse model and to determine the therapeutic window for the intermediate to mild forms of the disease. In the absence of such knowledge, adequate treatment will remain elusive and SMA will continue to be a leading cause of disability and death. The main focus of this application is to utilize mouse models to study the treatment of SMA, with the long-term goal of testing candidate therapies to correct the neuro-degenerative defect in patients. To this end, our lab has developed a new mild SMA mouse model (approximates SMA TYPE IV) with the mouse gene, Smn, mutated to produce low levels of the SMN protein. Furthermore, in order to generate the much needed intermediate SMA mouse model (similar to Type III in humans), we hypothesize that we will be able to further decrease the levels of SMN protein in our current mild model by using the recently published TSUNAMI technique (targeting splicing using negative ASOs to model illness).
We aim to determine the therapeutic window for the intermediate model that we generate.
The main focus of this application is to utilize mouse models to study the treatment window for Spinal Muscular Atrophy (SMA), a devastating neuro-degenerative disease that is a primary genetic cause of infant mortality in the United States. These models will be utilized to answer questions pertaining the therapeutic possibilities of SMN gene replacement and the critical difference in the timing of efficacious therapies in SMA disease of intermediate severity.