Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs

Abstract

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.

Advances in Treatment of Spinal Muscular Atrophy – New Phenotypes, New Challenges, New Implications for Care

“…An approach to altering the splicing of SMN2 and thus increasing the amount of functional SMNprotein is also taken by small molecules such as RG7916 (risdiplam) and LMI070 (branaplam). These compounds are taken orally, cross the blood-brain barrier, and have been shown to increase the amount of full length SMN-protein [48]. The most advanced compound is the pyridazine derivative RG7916 now being investigated in several trials: In the openlabel FIREFISH-study, 21 infants with SMA type 1 between 1 to 7 months of age received low-dose risdiplam (Part 1, n = 4) with the primary objective of safety-assessment, or a high dose (following Part 2, n = 17) with the primary objective of assessing efficacy (independent sitting after 12 months of treatment).…”

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges

“…Phase II/III trial (NCT02913482) Ratni et al, 2016Ratni et al, , 2018Poirier et al, 2018;Sturm et al, 2019 Branaplam (LMI070; NVS-SM1) Stabilizes the spliceosome and SMN2 pre-mRNA interactions to enhance SMN2 pre-mRNA splicing and thus increase expression of full-length SMN mRNA and functional protein Treatment of patients with SMA Phase I/II trial (NCT02268552) Palacino et al, 2015;Cheung et al, 2018;Dangouloff and Servais, 2019 Anthraquinones Binds to HIV TAR element to inhibit viral replication Treatment of HIV infection Preclinical development Ganser et al, 2018 Benzimidazoles (e.g., Isis-11) Binds to HCV IRES to inhibit viral replication…”

Spinal muscular atrophy - onasemnogene abeparvovec and other therapeutic options

“…Oznacza to, że wykazują działanie molekularne względem jednego bądź kilku ściśle wybranych genów [11]. Leki przyjmowane są doustnie i przekraczają barierę krew-mózg [34]. Działają systemowo, co daje im przewagę nad oligonukleotydami, gdyż białko SMN produkowane jest nie tylko w tkance nerwowej, ale również (w mniejszym stopniu) w innych tkankach.…”