title: Emerging therapies and challenges in spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease-modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease-modifying therapies will necessitate monitoring programs to determine the long-term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355-368.
authors.affiliation: Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, Sydney, Australia.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Farrar
authors.affiliation: Brain & Mind Centre and Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Susanna B
authors.initials: SB
authors.lastname: Park
authors.affiliation: Department of Neurology, Westmead Hospital and Western Clinical School, University of Sydney, Sydney, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Vucic
authors.affiliation: Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, Sydney, Australia.
authors.forename: Kate A
authors.initials: KA
authors.lastname: Carey
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburg, Edinburg, United Kingdom.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
authors.affiliation: Center for Human Genetics Research, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.affiliation: Brain & Mind Centre and Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kiernan
mesh_terms: D000818:Animals; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000209:etiology / Q000235:genetics / Q000628:therapy*