Vol 54, No 1 (2020)
Invited review article
Published online: 2020-01-10
Submitted: 2019-05-09
Accepted: 2019-10-19
Get Citation

Spinal muscular atrophy — new therapies, new challenges

Maria Jędrzejowska, Anna Kostera-Pruszczyk
DOI: 10.5603/PJNNS.a2019.0068
·
Pubmed: 31922583
·
Neurol Neurochir Pol 2020;54(1):8-13.

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Vol 54, No 1 (2020)
Invited review article
Published online: 2020-01-10
Submitted: 2019-05-09
Accepted: 2019-10-19

Abstract

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease with an autosomal recessive trait of inheritance and great variability of its clinical course – from the lethal congenital type (SMA0) to the adult-onset form (SMA4). The disease is associated with a deficiency of SMN protein, which is encoded by two genes SMN1 and SMN2. Clinical symptoms depend on mutations in the SMN1 gene. The number of copies of twin similar SMN2 gene, which produces small amounts of SMN protein, is the main phenotype modifier, which determines the clinical severity of the disease. Until recently, it was considered that spinal cord motoneurons undergo selective loss. Recent studies have shown the role of SMN protein in various cellular processes and the multisystemic character of SMA. The aim of the therapeutic strategies developed so far has been to increase the expression of SMN protein by modifying the splicing of SMN2 gene (intrathecally administered antisense oligonucleotide – nusinersen; orally available small molecules: RG7916 and LMI070 or SMN1 gene replacement therapy (AAV9-SMN). The first SMN2-directed antisense oligonucleotide (nusinersen) has demonstrated in clinical trials high efficiency, and it has now been registered. The best effects were obtained in patients who were introduced to the drug in the pre symptomatic period. Studies on other substances are ongoing. The great advances in SMA therapy and increased understanding of the pathogenesis of the disease raise hopes for changes to the natural history of the disease. Simultaneously, it increases awareness of the need to improve the standard of patient care and early diagnosis (newborn screening). Many questions (e.g. emerging phenotypes, combined therapies, systemic vs. intrathecal administration, long-term consequences, and complications of the therapy) will require further studies and observations.

Abstract

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease with an autosomal recessive trait of inheritance and great variability of its clinical course – from the lethal congenital type (SMA0) to the adult-onset form (SMA4). The disease is associated with a deficiency of SMN protein, which is encoded by two genes SMN1 and SMN2. Clinical symptoms depend on mutations in the SMN1 gene. The number of copies of twin similar SMN2 gene, which produces small amounts of SMN protein, is the main phenotype modifier, which determines the clinical severity of the disease. Until recently, it was considered that spinal cord motoneurons undergo selective loss. Recent studies have shown the role of SMN protein in various cellular processes and the multisystemic character of SMA. The aim of the therapeutic strategies developed so far has been to increase the expression of SMN protein by modifying the splicing of SMN2 gene (intrathecally administered antisense oligonucleotide – nusinersen; orally available small molecules: RG7916 and LMI070 or SMN1 gene replacement therapy (AAV9-SMN). The first SMN2-directed antisense oligonucleotide (nusinersen) has demonstrated in clinical trials high efficiency, and it has now been registered. The best effects were obtained in patients who were introduced to the drug in the pre symptomatic period. Studies on other substances are ongoing. The great advances in SMA therapy and increased understanding of the pathogenesis of the disease raise hopes for changes to the natural history of the disease. Simultaneously, it increases awareness of the need to improve the standard of patient care and early diagnosis (newborn screening). Many questions (e.g. emerging phenotypes, combined therapies, systemic vs. intrathecal administration, long-term consequences, and complications of the therapy) will require further studies and observations.

Get Citation

Keywords

spinal muscular atrophy, SMN1 gene, SMN protein, nusinersen, gene therapy

About this article
Title

Spinal muscular atrophy — new therapies, new challenges

Journal

Neurologia i Neurochirurgia Polska

Issue

Vol 54, No 1 (2020)

Pages

8-13

Published online

2020-01-10

DOI

10.5603/PJNNS.a2019.0068

Pubmed

31922583

Bibliographic record

Neurol Neurochir Pol 2020;54(1):8-13.

Keywords

spinal muscular atrophy
SMN1 gene
SMN protein
nusinersen
gene therapy

Authors

Maria Jędrzejowska
Anna Kostera-Pruszczyk

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