Antimyostatin; clinical trials; drug repositioning; gene therapy; nusinersen; onasemnogene abeparvovec; risdiplam; smn1 gene; spinal muscular atrophy; Drugs, Investigational; SMN1 protein, human; SMN2 protein, human; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein; Animals; Child; Drugs, Investigational/pharmacology; Humans; Muscular Atrophy, Spinal/drug therapy; Muscular Atrophy, Spinal/genetics; Muscular Atrophy, Spinal/physiopathology; Survival of Motor Neuron 1 Protein/genetics; Survival of Motor Neuron 2 Protein/genetics; Drug Development; Muscular Atrophy, Spinal; Pharmacology; Pharmacology (medical); General Medicine
Abstract :
[en] INTRODUCTION: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative neuromuscular disease that presents primarily in children. Abnormalities in the SMN1 gene cause reduced levels of the survival motor neuron (SMN) protein, while a second gene, SMN2, produces low levels of functional SMN protein. Currently available drugs do not cure, so a significant unmet need remains for patients treated after symptom onset.
AREAS COVERED: Drugs available in the clinic, investigational agents and key questions for researchers are discussed. A pragmatic search of the literature was performed to identify therapies in late stages of preclinical, or in early stages of clinical development. This list was compared to the CureSMA pipeline for completeness. Drugs approved for indications that have potential for impact for SMA were included. These drugs target the primary deficiency in SMN protein or other pathways involved in SMA pathophysiology that are not SMN-protein dependent.
EXPERT OPINION: Children treated after the onset of symptoms continue to have significant disability. Given the heterogeneity of the population phenotype evidenced by variable response to initial therapy, age at treatment onset and the need to demonstrate added value beyond approved therapeutics, the clinical development of new drugs will be challenging.
Disciplines :
Neurology
Author, co-author :
Servais, Laurent ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie ; MDUK Neuromuscular Center, Department of Paediatrics, University of Oxford, Oxford, UK
Baranello, Giovanni; Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
Scoto, Mariacristina; Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
DARON, Aurore ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie
Oskoui, Maryam; Departments of Pediatrics and Neurology & Neurosurgery, McGill University, Montreal, QC, Canada
Language :
English
Title :
Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities.
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