NVS-SM2

NVS-SM2 is a potent, orally active and brain-penetrant SMN2 splicing enhancer with an EC₅₀ of 2 nM for SMN. NVS-SM2 enhances U1-pre-mRNA association. NVS-SM2 promotes exon 7 inclusion and restores normal survival motor neuron (SMN) protein expression. NVS-SM2 can be used for spinal muscular atrophy (SMA) research^[1][2]. IC50 & Target: EC50: 5 nM (SMN)^[1] In Vitro: For NVS-SM2, the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition^[1]. In Vivo: NVS-SM2 (0.1-1 mg/kg; s.c.; for 30 days) treatment extends survival in a severe SMA mouse model^[2].
Pharmacokinetic analysis demonstrate that NVS-SM2 is readily available in the brain after IV and oral (PO) administration in mouse and rat with T_max of 3 h after PO with 3 mg/kg in mice, and NVS-SM2 treatment induces a 1.5-fold increase in SMN protein levels in the mouse brain^[1].