Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (<i>SMN2</i>) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)

Ratni, Hasane; Ebeling, Martin; Baird, John D.; Bendels, Stefanie; Bylund, Johan; Chen, Karen S.; Denk, Nora; Feng, Zhichun; Green, Luke; Guérard, Melanie; Jablonski, Philippe; Jacobsen, Björn; Khwaja, Omar; Kletzl, Heidemarie; Ko, Chien‐Ping; Kustermann, Stefan; Marquet, Anne; Metzger, Friedrich; Mueller, Barbara M.; Naryshkin, Nikolai; Paushkin, Sergey; Pinard, Emmanuel; Poirier, Agnès; Reutlinger, Michael; Weetall, Marla; Zeller, Andreas; Zhao, Xin; Mueller, Lutz

doi:10.1021/acs.jmedchem.8b00741

Cited by 360 publications

(387 citation statements)

References 33 publications

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“…In Study 5, SMN protein level increases were measured relative to SMN levels in heterozygous control animals and a correlation was observed between increase in SMN protein in blood and in brain. In the same study, risdiplam was shown to improve phenotype and motor function, to prolong survival and to increase body weight gain in SMNΔ7 mice …”

Section: Resultsmentioning

confidence: 82%

“…Risdiplam structure and method of synthesis can be found in reference . RG7800 structure and method of synthesis can be found in reference …”

Section: Methodsmentioning

confidence: 99%

“…Risdiplam structure and method of synthesis can be found in reference. 17 RG7800 structure and method of synthesis can be found in reference. 16 The rodent Mdr1a is a murine protein and shares 95% amino acid sequence identity with the rat Mdr1a, 19 henceforth referred as "rodent" Mdr1a throughout the manuscript.…”

Section: Methodsmentioning

confidence: 99%

“…Risdiplam is an orally administered, small‐molecule SMN2 pre‐mRNA splicing modifier, optimized in terms of pharmacokinetic (PK) characteristics and with enhanced specificity toward SMN2 exon 7 splicing relative to other SMN2 splicing modifiers . Risdiplam demonstrated a higher in vitro and in vivo efficacy in cellular and mouse models of SMA, a larger safety window in preclinical models (including to off‐target retinal findings) and an improved human PK profile compared with RG7800 . Risdiplam increases SMN2FL mRNA production and distributes into the central nervous system (CNS) and peripheral tissues by avoiding interaction with human multidrug resistance protein 1 (MDR1); a transport protein that restricts brain exposure.…”

Section: Introductionmentioning

confidence: 99%

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

Poirier

Weetall

Heinig

et al. 2018

Pharmacology Res & Perspec

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129

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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.

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Section: Resultsmentioning

confidence: 82%

“…Risdiplam structure and method of synthesis can be found in reference . RG7800 structure and method of synthesis can be found in reference …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Poirier

Weetall

Heinig

et al. 2018

Pharmacology Res & Perspec

Self Cite

129

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“…It is also possible that the restoration of SMN levels to normal range in blood does not necessarily correlate with the functional recovery, but might predict only the long-term effect of a given treatment. Studies on more clinically effective compounds, such as risdiplam, could clarify whether the molecular response may predict the clinical outcome 34. Finally, the utility of SMN-independent biomarkers is still unproven, such as the SMA-MAP, a panel of plasma protein related to the clinical function of patients, or some miRNAs identified by others and ourselves 35 36.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal evaluation of SMN levels as biomarker for spinal muscular atrophy: results of a phase IIb double-blind study of salbutamol

Tiziano¹,

Lomastro²,

Abiusi³

et al. 2018

J Med Genet

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BackgroundSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, due to the loss of function of the survival motor neuron (SMN1) gene. The first treatment for the condition, recently approved, is based on the reduction of exon 7 skipping in mRNAs produced by a highly homologous gene (SMN2). The primary objective of the present study was to evaluate the applicability of the dosage of SMN gene produts in blood, as biomarker for SMA, and the safety of oral salbutamol, a beta2-adrenergic agonist modulating SMN2 levels.MethodsWe have performed a 1-year multicentre, double-blind, placebo-controlled study with salbutamol in 45 adult patients with SMA. Patients assumed 4 mg of salbutamol or placebo/three times a day. Molecular tests were SMN2 copy number, SMN transcript and protein levels. We have also explored the clinical effect, by the outcome measures available at the time of study design.ResultsThirty-six patients completed the study. Salbutamol was safe and well tolerated. We observed a significant and progressive increase in SMN2 full-length levels in peripheral blood of the salbutamol-treated patients (p<0.00001). The exploratory analysis of motor function showed an improvement in most patients.ConclusionsOur data demonstrate safety and molecular efficacy of salbutamol. We provide the first longitudinal evaluation of SMN levels (both transcripts and protein) in placebo and in response to a compound modulating the gene expression: SMN transcript dosage in peripheral blood is reliable and may be used as pharmacodynamic marker in clinical trials with systemic compounds modifying SMN2levels.Trial registration numberEudraCT no. 2007-001088-32.

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Targeting RNA‐binding proteins with small molecules: Perspectives, pitfalls and bifunctional molecules

Kang

2023

FEBS Letters

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RNA‐binding proteins (RBPs) play vital roles in organisms through binding with RNAs to regulate their functions. Small molecules affecting the function of RBPs have been developed, providing new avenues for drug discovery. Herein, we describe the perspectives on developing small molecule regulators of RBPs. The following types of small molecule modulators are of great interest in drug discovery: small molecules binding to RBPs to affect interactions with RNA molecules, bifunctional molecules binding to RNA or RBP to influence their interactions, and other types of molecules that affect the stability of RNA or RBPs. Moreover, we emphasize that the bifunctional molecules may play important roles in small molecule development to overcome the challenges encountered in the process of drug discovery.

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Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)

Cited by 360 publications

References 33 publications

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

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

Longitudinal evaluation of SMN levels as biomarker for spinal muscular atrophy: results of a phase IIb double-blind study of salbutamol

Targeting RNA‐binding proteins with small molecules: Perspectives, pitfalls and bifunctional molecules

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