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Spinal muscular atrophy—recent therapeutic advances for an old challenge

Key Points

  • Spinal muscular atrophy (SMA) is the most common cause of infant death resulting from genetic defect

  • Children affected by SMA present with various degrees of muscular wasting, along with a complex profile of accompanying symptoms

  • No effective therapy for SMA is currently available in clinical practice

  • An increasing comprehension of SMA pathophysiology, including the characterization of SMN1 and SMN2 genes and SMN protein functions, has led to the development of multiple experimental therapeutic strategies

  • Therapeutic approaches aim to replace or correct the faulty SMN1 gene, promote exon 7 inclusion in SMN2, increase SMN2 promoter activity, or stabilize and protect full-length and Δ7 SMN proteins

  • Worldwide, several clinical trials evaluating the efficacy of these approaches are ongoing

Abstract

In the past decade, improved understanding of spinal muscular atrophy (SMA) aetiopathogenesis has brought us to a historical turning point: we are at the verge of development of disease-modifying treatments for this hitherto incurable disease. The increasingly precise delineation of molecular targets within the survival of motor neuron (SMN) gene locus has led to the development of promising therapeutic strategies. These novel avenues in treatment for SMA include gene therapy, molecular therapy with antisense oligonucleotides, and small molecules that aim to increase expression of SMN protein. Stem cell studies of SMA have provided an in vitro model for SMA, and stem cell transplantation could be used as a complementary strategy with a potential to treat the symptomatic phases of the disease. Here, we provide an overview of established data and novel insights into SMA pathogenesis, including discussion of the crucial function of the SMN protein. Preclinical evidence and recent advances from ongoing clinical trials are thoroughly reviewed. The final remarks are dedicated to future clinical perspectives in this rapidly evolving field, with a broad discussion on the comparison between the outlined therapeutic approaches and the remaining open questions.

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Figure 1: Overview of the clinical characteristics of SMA.
Figure 2: Differential diagnoses in suspected SMA.
Figure 3: iPSC-derived motor neurons exhibit SMA-like features.
Figure 4: Therapeutic strategies in SMA.

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Acknowledgements

The financial support from Ministry of Health (GR-2009-1483560) and Cariplo grant (2012-0513) to S.C., and Telethon grant (GGP14025) to M.N. are gratefully acknowledged. All authors gratefully acknowledge the support from Associazione Amici del Centro Dino Ferrari.

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S.C. and I.F. researched data for the article. S.C., I.F. and G.P.C. wrote the manuscript. All authors substantially contributed to discussion of content and reviewing, editing and revising of manuscript.

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Correspondence to Stefania Corti.

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Faravelli, I., Nizzardo, M., Comi, G. et al. Spinal muscular atrophy—recent therapeutic advances for an old challenge. Nat Rev Neurol 11, 351–359 (2015). https://doi.org/10.1038/nrneurol.2015.77

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