Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy.
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.
Hastings
Michelle L
ML
Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60044, USA. michelle.hastings@rosalindfranklin.edu
Berniac
Joel
J
Liu
Ying Hsiu
YH
Abato
Paul
P
Jodelka
Francine M
FM
Barthel
Lea
L
Kumar
Sujatha
S
Dudley
Caroline
C
Nelson
Mark
M
Larson
Kelley
K
Edmonds
Jason
J
Bowser
Todd
T
Draper
Michael
M
Higgins
Paul
P
Krainer
Adrian R
AR
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*
C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein; D013754:Tetracyclines