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Review
. 2022 Jun 16:16:1865-1883.
doi: 10.2147/DDDT.S214174. eCollection 2022.

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

Helgi Thor Hjartarson  1 , Kristofer Nathorst-Böös  1 , Thomas Sejersen  1   2
Affiliations
Review

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

Helgi Thor Hjartarson et al. Drug Des Devel Ther. .

Abstract

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: disease-modifying; gene therapy; spinal muscular atrophy; treatment.

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Conflict of interest statement

Thomas Sejersen: Recipient of honoraria received for lectures or consultancy from Biogen, Novartis, PTC Therapeutics, Sarepta Therapeutics, Roche, Hansa Biopharma and Sanofi Genzyme. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Schematic illustration of SMA types, maximal milestones achieved within each type, as well as the most typical SMN2 copy numbers for respective type.
Figure 2
Figure 2
Simplified illustration of the mechanism of action of the three disease modifying therapies for SMA: Onasemnogene abeparvovec, nusinersen and risdiplam.
See this image and copyright information in PMC

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