The goal of this project is to discover small molecules that increase the splicing of exon 7 of the SMN2 gene pre-mRNA. The generation of full length SMN2 transcripts can potentially compensate the loss of the SMN1 gene in Spinal Muscular Atrophy (SMA) patients. Previous studies of cell and animal models show that increased human SMN2 gene dosage, transcription rate, and exon 7 inclusion result in elevated SMN protein levels and can compensate for the loss of the SMN1 gene in SMA. By high throughput screening of compound libraries we have identified 150 compounds modulating the splicing of SMN2 exon 7, including 76 compounds derived from combinatorial chemistry libraries. We now propose to explore structural analogues of these compounds identified in the preliminary screens, to discover more potent modulators of SMN2 exon 7 splicing. These will constitute potential lead compounds in the development of SMA therapeutics. Due to the combinatorial regulation of alternative pre-mRNA splicing, compounds targeting the splicing apparatus are likely to affect the splicing of a multiple exons. This may lead to undesired side effects and preclude the therapeutic use of certain compounds. To address this issue we will determine the global effect on splicing of each compound class using microarrays.
Our aims are to:
Aim 1 : To identify potent modulators of SMN2 exon 7 splicing by screening structural analogues of compounds already identified in the preliminary high throughput screening experiments. The screening will be performed using high throughput RT-PCR.
Aim 2 : To determine the global effect on splicing of representative compounds from each class using microarrays.
Small molecules that improve the splicing of SMN2 exon 7 are promising therapeutics for spinal muscular atrophy. Our preliminary work has identified several classes of compounds that can modulate SMN2 exon 7 splicing. In order to identify the most potent therapeutic agents we will explore more small molecules structurally related to these classes.
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