pyrimidinones and Muscular-Atrophy--Spinal

Spinal muscular atrophy (SMA) is the leading genetic cause of infant and toddler mortality, and there is currently no approved therapy available. SMA is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. These mutations or deletions result in low levels of functional SMN protein. SMN2, a paralogous gene to SMN1, undergoes alternative splicing and exclusion of exon 7, producing an unstable, truncated SMNΔ7 protein. Herein, we report the identification of a pyridopyrimidinone series of small molecules that modify the alternative splicing of SMN2, increasing the production of full-length SMN2 mRNA. Upon oral administration of our small molecules, the levels of full-length SMN protein were restored in two mouse models of SMA. In-depth lead optimization in the pyridopyrimidinone series culminated in the selection of compound 3 (RG7800), the first small molecule SMN2 splicing modifier to enter human clinical trials.

Topics: Alternative Splicing; Animals; Exons; Humans; Mice; Muscular Atrophy, Spinal; Pyrimidinones; RNA, Messenger; Survival of Motor Neuron 2 Protein

Topics: Alternative Splicing; Animals; Coumarins; Humans; Isocoumarins; Longevity; Muscular Atrophy, Spinal; Pyrimidinones; Small Molecule Libraries; Survival of Motor Neuron 2 Protein

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.

Topics: Administration, Oral; Alternative Splicing; Animals; Cells, Cultured; Coumarins; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Isocoumarins; Longevity; Mice; Muscular Atrophy, Spinal; Pyrimidinones; RNA, Messenger; Sequence Deletion; Small Molecule Libraries; Survival of Motor Neuron 2 Protein

Topics: Alternative Splicing; Animals; Coumarins; Humans; Isocoumarins; Longevity; Muscular Atrophy, Spinal; Pyrimidinones; Small Molecule Libraries; Survival of Motor Neuron 2 Protein