Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disorder, and is the most common lethal monogenic disease of infants and toddlers. SMA is caused by the loss of the survival motor neuron 1 (SMN1) gene. A compensatory gene called SMN2 includes a single nucleotide mutation leading to a mis-spliced RNA transcript and an unstable truncated SMN protein. Infant SMA patients suffer from degeneration of motor neurons, loss of peripheral and central motor control, and have a reduced life expectancy. Recently, much progress has been made towards disease modifying treatments for SMA. We describe our identification of the pyridazine scaffold from a high throughput screen, and the optimization work leading to the discovery of our clinical candidate LMI070. Additionally, we present the elucidation of its mechanism of action, correcting the splicing defect in the SMN2 gene through stabilization of the spliceosome/pre-mRNA complex. In mouse models, LMI070 increased expression of full length SMN protein in the brain of SMA mice, and extended overall survival. LMI070 is currently being evaluated for efficacy in infant SMA patients, and initial clinical results will be presented.

Spinal muscular atrophy: Advancing small molecule splicing modulators from phenotypic screen to the clinic

256th National Meeting (2018)

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