RESUMEN
Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene. A second gene, SMN2, produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1. Risdiplam (RG7916; RO7034067) is an orally administered, small-molecule SMN2 pre-mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n = 90), rats (n = 148), and monkeys (n = 24). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39 weeks. A parallel dose-dependent increase in SMN protein levels was seen in CNS and peripheral tissues in two SMA mouse models dosed with risdiplam. These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients' blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues.
Asunto(s)
Compuestos Azo/farmacocinética , Atrofia Muscular Espinal/tratamiento farmacológico , Fármacos Neuromusculares/farmacocinética , Pirimidinas/farmacocinética , Empalme del ARN/efectos de los fármacos , Proteína 2 para la Supervivencia de la Neurona Motora/metabolismo , Animales , Compuestos Azo/líquido cefalorraquídeo , Compuestos Azo/farmacología , Compuestos Azo/uso terapéutico , Encéfalo/metabolismo , Encéfalo/patología , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Exones/efectos de los fármacos , Exones/genética , Femenino , Humanos , Macaca fascicularis , Células de Riñón Canino Madin Darby , Masculino , Ratones , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Fármacos Neuromusculares/líquido cefalorraquídeo , Fármacos Neuromusculares/farmacología , Fármacos Neuromusculares/uso terapéutico , Pirimidinas/líquido cefalorraquídeo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas , Ratas Wistar , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Porcinos , Distribución TisularRESUMEN
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.