Spinal Muscular Atrophy (SMA) is a neurodegenerative disease that constitutes the greatest source of genetic mortality in infants. There is currently no method of treatment or prevention and incidence can be as high as 1 in 6000-10,000 births. SMA causes debilitating muscle weakness and, in severe cases, respiratory distress and death. SMA is caused by low levels of survival motor neuron (SMN) protein. SMN is encoded by two genes, SMN1 and SMN2. SMN protein is required for survival and SMA is caused by deletions or mutations of SMN1, but early lethality of this mutation is prevented by the paralogous gene, SMN2. These two genes are nearly identical, however, a key divergence lies in a single nucleotide difference, which hinders exon inclusion in SMN2 during pre-mRNA splicing. Therefore, SMN2 produces mainly truncated proteins, which are degraded. Administration of the deficient protein to severe SMA mouse models attenuates disease severity. However, there is evidence that the time point at which these treatments are administered plays a vital role in how effectively they combat SMA. Most studies to date have been conducted in severe SMA mouse models, which have a two-week window for observation before death or a mild SMA model, which has a normal life span. Currently our laboratory has developed a mild SMA mouse model with the mouse gene, Smn, mutated to resemble the human SMN2, which causes truncated proteins, and consequently resembles a mild form of SMA.
We aim to determine the therapeutic window for SMN replacement in our current mild SMA mouse model. We hypothesize that ability for disease rescue will significantly decrease after disease onset. SMA is a disease with a broad range of severity and onset. Therefore, it is paramount to develop an intermediate SMA mouse model to determine if all severities of SMA can be treated in a similar way. We hypothesize that we will be able to create an intermediate SMA mouse model from our current mild model, by using antisense oligonucleotides (ASO) to decrease the number of full-length proteins from the mutated Smn locus. I have designed an ASO that targets an important area for splice site recognition, interfering with the ability for th corresponding exon to be included in the final transcript. I have tested the ASO in cultured cells and have generated preliminary data that shows a decrease in production of full-length transcripts. Our goal is to identify a therapeutic system to alleviate symptoms of this traumatic disease in order to improve the quality and length of the lives of those suffering from SMA. My objective in this application is to systematically determine the critical time points for SMN proten in development to determine when treatments for the disease will be most effective and to create an intermediate mouse model to allow study of all SMA disease severities.
Spinal Muscular Atrophy (SMA) is a neurodegenerative disease that constitutes the greatest source of genetic mortality in infants. Those that survive past infancy are plagued with debilitating muscle weakness and shortened life span. There is currently no method of treatment or prevention and incidence can be as high as 1 in 6000-10,000 births. This research proposal will provide a therapeutic window for late-onset SMA as well as a new model for intermediate-severity SMA. Since SMA is a disease manifested in a variety of intensities and ages of onset, it is important to have access to a full spectrum of intensity models.