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Published in: Neurological Research and Practice 1/2022

Open Access 01-12-2022 | Amyotrophic Lateral Sclerosis | Review

Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders

Authors: Sibylle Jablonka, Luisa Hennlein, Michael Sendtner

Published in: Neurological Research and Practice | Issue 1/2022

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Abstract

Background

Major efforts have been made in the last decade to develop and improve therapies for proximal spinal muscular atrophy (SMA). The introduction of Nusinersen/Spinraza™ as an antisense oligonucleotide therapy, Onasemnogene abeparvovec/Zolgensma™ as an AAV9-based gene therapy and Risdiplam/Evrysdi™ as a small molecule modifier of pre-mRNA splicing have set new standards for interference with neurodegeneration.

Main body

Therapies for SMA are designed to interfere with the cellular basis of the disease by modifying pre-mRNA splicing and enhancing expression of the Survival Motor Neuron (SMN) protein, which is only expressed at low levels in this disorder. The corresponding strategies also can be applied to other disease mechanisms caused by loss of function or toxic gain of function mutations. The development of therapies for SMA was based on the use of cell culture systems and mouse models, as well as innovative clinical trials that included readouts that had originally been introduced and optimized in preclinical studies. This is summarized in the first part of this review. The second part discusses current developments and perspectives for amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease, as well as the obstacles that need to be overcome to introduce RNA-based therapies and gene therapies for these disorders.

Conclusion

RNA-based therapies offer chances for therapy development of complex neurodegenerative disorders such as amyotrophic lateral sclerosis, muscular dystrophies, Parkinson’s and Alzheimer’s disease. The experiences made with these new drugs for SMA, and also the experiences in AAV gene therapies could help to broaden the spectrum of current approaches to interfere with pathophysiological mechanisms in neurodegeneration.
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Metadata
Title
Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders
Authors
Sibylle Jablonka
Luisa Hennlein
Michael Sendtner
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Neurological Research and Practice / Issue 1/2022
Electronic ISSN: 2524-3489
DOI
https://doi.org/10.1186/s42466-021-00162-9

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