Disease Modifying Therapies for the Management of Children with Spinal Muscular Atrophy (5q SMA): An Update on the Emerging Evidence

Drug Design, Development and Therapy

关键词: spinal muscular atrophy;    treatment;    disease-modifying;    gene therapy;   

DOI  :  

来源: DOAJ

【 摘 要 】

Helgi Thor Hjartarson,1 Kristofer Nathorst-Böös,1 Thomas Sejersen1,2 1Department of Neuropediatrics, Astrid Lindgren Children´s Hospital, Karolinska University Hospital, Stockholm, Sweden; 2Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, SwedenCorrespondence: Thomas Sejersen, Department of Women’s and Children’s Health, Karolinska Institute, Karolinska Vägen 37A, Stockholm, 171 76, Sweden, Tel [phone], Email [e-mail]: SMA (5q SMA) is an autosomal recessive neuromuscular disease with an estimated incidence of approximately 1 in 11,000 live births, characterized by progressive degeneration and loss of α-motor neurons in the spinal cord and brain stem, resulting in progressive muscle weakness. The disease spectrum is wide, from a serious congenital to a mild adult-onset disease. SMA is caused by biallelic mutations in the SMN1 gene and disease severity is modified primarily by SMN2 copy number. Before the advent of specific disease altering treatments, SMA was the second most common fatal autosomal recessive disorder after cystic fibrosis and the most common genetic cause of infant mortality. Nusinersen, risdiplam, and onasemnogene abeparvovec are presently the only approved disease modifying therapies for SMA, and the aim of this review is to discuss their mode of action, effects, safety concerns, and results from real-world experience. All exert their action by increasing the level of SMN protein in lower motor neuron. Nusinersen and risdiplam by modifying the SMN2 gene product, and onasemnogene abeparvovec by delivering SMN1 gene copies into cells. All have an established clinical efficacy. An important feature shared by all three is that early intervention is associated with a better treatment outcome, such that in cases where treatment is initiated in an early pre-symptomatic period, it may result in normal – or almost normal – motor development. Thus, early diagnosis followed by swift initiation of treatment is fundamental for the treatment response and consequently long-term prognosis in SMA type 1, and probably SMA type 2. The same principle similarly applies to the milder phenotypes. All three therapies are relatively novel, with risdiplam being the latest addition. Except for nusinersen, real-world data are still scarce, and long-term data are quite naturally lacking.Keywords: spinal muscular atrophy, treatment, disease-modifying, gene therapy

【 授权许可】

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