title: Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy.
abstract: 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.
authors.affiliation: Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60044, USA. michelle.hastings@rosalindfranklin.edu
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Hastings
authors.forename: Joel
authors.initials: J
authors.lastname: Berniac
authors.forename: Ying Hsiu
authors.initials: YH
authors.lastname: Liu
authors.forename: Paul
authors.initials: P
authors.lastname: Abato
authors.forename: Francine M
authors.initials: FM
authors.lastname: Jodelka
authors.forename: Lea
authors.initials: L
authors.lastname: Barthel
authors.forename: Sujatha
authors.initials: S
authors.lastname: Kumar
authors.forename: Caroline
authors.initials: C
authors.lastname: Dudley
authors.forename: Mark
authors.initials: M
authors.lastname: Nelson
authors.forename: Kelley
authors.initials: K
authors.lastname: Larson
authors.forename: Jason
authors.initials: J
authors.lastname: Edmonds
authors.forename: Todd
authors.initials: T
authors.lastname: Bowser
authors.forename: Michael
authors.initials: M
authors.lastname: Draper
authors.forename: Paul
authors.initials: P
authors.lastname: Higgins
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
mesh_terms: D000818:Animals; D005091:Exons; D006801:Humans; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics; D012326:RNA Splicing / Q000187:drug effects*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics; D013754:Tetracyclines / Q000494:pharmacology*
chemical_list: C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein; D013754:Tetracyclines