SMN2 Silent Mutation Knock-in: New SMA Mouse Model-Better Therapies

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DESCRIPTION (provided by applicant): Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuro-degenerative disease that is the primary genetic cause of infant mortality in the United States. Absence of the survival of motor neuron-1 gene (SMN1) gene product as a result of deletion or mutation leads to the disease. The SMN1 protein is necessary for motor neuron survival. The human genome harbors a nearly identical gene, SMN2, that is functionally redundant with SMN1 and could potentially rescue the disease phenotype. The SMN2 gene, however, is expressed at greatly reduced levels due to ineffective processing of the SMN2 RNA product. Specifically, the SMN2 varies from the SMN1 gene at a single nucleotide positioned in exon 7. This altered nucleotide leads to decreased recognition of exon 7 by the splicing machinery and results, ultimately, in skipping of the exon and the generation of a non-functional protein product. Correction of the SMN2 splicing phenotype is therefore a powerful therapeutic option to reinstate SMN activity in the correct time and place in SMA patients. However, no animal models exist to accurately test this therapeutic option. The primary goal of this proposal is to generate a SMA mouse model that contains the human SMN2 exon 7 point mutation in the mouse Smn gene. We hypothesize that this mouse model will more precisely recapitulate the human SMA condition relative to splicing of the SMN2 gene. Furthermore this model is necessary to address potential therapies aimed at correcting SMN2 splicing, and to evaluate the timing and dosage of SMN replacement therapies. We will use the new and improved SMA model to address the proper timing for the administration of such therapies. The main focus of this proposal is to generate mouse models for Spinal Muscular Atrophy (SMA), a devastating neuro-degenerative disease that is a primary genetic cause of infant mortality in the United States. In order to model the disease, we plan to generate a mouse model that has an alteration in the survival of motor neuron (SMN) gene that is known to lead to the SMA disease in humans. This mouse will be utilized to answer many questions pertaining the therapeutic possibilities of SMN gene replacement therapies with the long-term goal of testing candidate therapies to correct the neuro- degenerative defect in patients.