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Review
. 2022 Jan 4;4(1):2.
doi: 10.1186/s42466-021-00162-9.

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

Sibylle Jablonka  1 , Luisa Hennlein  2 , Michael Sendtner  3
Affiliations
Review

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

Sibylle Jablonka et al. Neurol Res Pract. .

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.

Keywords: Alzheimer disease; Amyotrophic lateral sclerosis; Clinical trial; Gene therapy; Motoneuron disease; Muscular disease; Muscular dystrophy; Neurodegenerative disease; Parkinson disease; Spinal muscular atrophy.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Genetic cause of spinal muscular atrophy (SMA). The human survival motor neuron genes (SMN1 and SMN2) are located in an inverse duplicated region on chromosome 5q13.2. On DNA level, the two genes only differ by one functionally relevant nucleotide exchange within exon 7. This transition from C to T results in the generation of an exonic splicing silencer (ESS) site leading to exon 7 skipping on mRNA level. While SMN1 codes for the functional, full-length SMN protein, SMN2 predominantly (~ 90%) produces a truncated, non-functional version of the protein. SMA is caused by homozygous deletions of SMN1 resulting in highly reduced SMN protein levels. However, the number of SMN2 copies that determines the amount of functional SMN protein can modify disease severity
Fig. 2
Fig. 2
Gene therapies in SMA. Overview of the currently available therapies for spinal muscular atrophy (SMA): Antisense Oligonucleotide (ASO: Nusinersen), small molecule (Risdiplam), AAV9 gene delivery approach (Onasemnogene abeparvovec)—and corresponding clinical trials
Fig. 3
Fig. 3
Timeline of the current Onasemnogene abeparvovec/Zolgensma™ trials. Illustration of the different clinical trials (clinical trials 1 and 3, LFTU) with Onasemnogene abeparvovec/Zolgensma™ according to their scheduled duration
Fig. 4
Fig. 4
Different therapeutic strategies in familial forms of amyotrophic lateral sclerosis. Illustration of the different ASO and AAV approaches for the SOD1-, C9ORF72-, and FUS-ALS forms
See this image and copyright information in PMC

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