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 smallmolecule 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.

Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy

“…To this end, much effort has been devoted to identifying agents that enhance SMN2 expression in cell-free assays (29), cultured cells (30)(31)(32)(33), model organisms (29,(34)(35)(36), and even in human patients (37,38). These studies have established the feasibility not just of SMN2 modulation but also of direct SMN augmentation.…”

Splicing-factor alterations in cancers

“…For example, several groups identified compounds that enhance SMN2 exon 7 splicing to promote the production of a full-length SMN protein (Hastings et al 2009;Naryshkin et al 2014;Palacino et al 2015), an approach with therapeutic potential for spinal muscular atrophy. Likewise, small molecules that promote the inclusion of exon 20 in the IKBKAP pre-mRNA have been reported, and may have therapeutic utility for familial dysautonomia (Yoshida et al 2015).…”

Repair of pre-mRNA splicing

“…Another drug found to improve SMN2 exon 7 inclusion is a tetracycline-like compound, termed PTK-SMA1. 115 However, this compound does not appear to cross the blood-brain barrier, so that further chemical derivatives or sophisticated modes of application such as cerebrospinal fluid instillation may be required.…”