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Tetracycline derivatives increase exon 7 splicing during RNA processing of the spinal muscular atrophy–modifying gene SMN2, which may prove therapeutically useful. Correcting Splicing to Prevent Spinal Muscular Atrophy Even before birth, a child with the most severe form of spinal muscular atrophy (SMA) may be frail, so that the mother feels only faint fetal movements during the last months of pregnancy. After birth, children with this autosomal recessive disease exhibit weak muscles, swallowing difficulties, and respiratory problems, often dying within the first 2 years of life. These symptoms are caused by the degeneration of certain motor neurons in the spinal cord, resulting in muscle weakness and shrinking. There is no cure or effective therapy for SMA, which kills more infants than any other genetic disorder. Now, Krainer and colleagues describe a compound with promise as an SMA therapeutic. SMA is usually caused by loss-of-function mutations in the SMN1 gene, which encodes a protein that aids in the assembly of the spliceosome. This large protein-RNA complex removes introns from RNA transcripts to create mature mRNAs. An inadequate amount of SMN protein causes SMA, but it is not clear why the deficiency selectively affects spinal cord motor neurons. Cells contain a second source of the SMN protein, the SMN2 gene. Because of a single nucleotide change in SMN2, its RNA transcript is usually spliced incorrectly, such that exon 7 is left out; the encoded truncated protein is quite unstable. Thus, one way to treat SMA would be to correct SMN2 splicing. Although compounds have been identified that increase the production of full-length SMN protein from SMN2, they act in a relatively nonspecific manner; some are toxic. A better possibility might be a drug that specifically alters splicing, potentially reducing side effects. The Hastings and Krainer labs, in collaboration with Paratek Pharmaceuticals, sought to identify a small molecule that specifically improves exon 7 splicing of SMN2 RNA in a cell-free assay. In a screen, they found one compound, a tetracycline derivative called PTK-SMA1, that could do this. PTK-SMA1 appears to stimulate exon 7 splicing in SMN1/2 specifically, not affecting splicing of other tested substrates. The researchers determined that PTK-SMA1 increases SMN protein concentrations both in fibroblasts derived from an SMA patient and in mouse models of SMA. Because PTK-SMA1 does not cross the blood-brain barrier but would need to do so in order to be therapeutically useful, the researchers now aim to modify PTK-SMA1 to achieve that end. Furthermore, as RNA splicing defects may contribute to other diseases, additional tetracycline derivatives that can repair specific splicing defects could potentially be identified and prove useful. There is at present no cure or effective therapy for spinal muscular atrophy (SMA), a neurodegenerative disease that is the leading genetic cause of infant mortality. SMA usually results from loss of the SMN1 (survival of motor neuron 1) gene, which leads to selective motor neuron degeneration. SMN2 is nearly identical to SMN1 but has a nucleotide replacement that causes exon 7 skipping, resulting in a truncated, unstable version of the SMA protein. SMN2 is present in all SMA patients, and correcting SMN2 splicing is a promising approach for SMA therapy. We identified a tetracycline-like compound, PTK-SMA1, which stimulates exon 7 splicing and increases SMN protein levels in vitro and in vivo in mice. Unlike previously identified molecules that stimulate SMN production via SMN2 promoter activation or undefined mechanisms, PTK-SMA1 is a unique therapeutic candidate in that it acts by directly stimulating splicing of exon 7. Synthetic small-molecule compounds such as PTK-SMA1 offer an alternative to antisense oligonucleotide therapies that are being developed as therapeutics for a number of disease-associated splicing defects.

Tetracyclines That Promote SMN2 Exon 7 Splicing as Therapeutics for Spinal Muscular Atrophy