LMI070 HCl

Description: LMI070 (also known as Branaplam and NVS-SM1) is a potent, orally active, small-molecule enhancer of SMN2 (survival of motor neuron-2) splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. 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. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.