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Review
. 2022 Jun 29;11(13):2066.
doi: 10.3390/cells11132066.

Gene Therapy in Amyotrophic Lateral Sclerosis

Ton Fang  1 , Goun Je  1 , Peter Pacut  1 , Kiandokht Keyhanian  1 , Jeff Gao  1 , Mehdi Ghasemi  1
Affiliations
Review

Gene Therapy in Amyotrophic Lateral Sclerosis

Ton Fang et al. Cells. .

Abstract

Since the discovery of Cu/Zn superoxide dismutase (SOD1) gene mutation, in 1993, as the first genetic abnormality in amyotrophic lateral sclerosis (ALS), over 50 genes have been identified as either cause or modifier in ALS and ALS/frontotemporal dementia (FTD) spectrum disease. Mutations in C9orf72, SOD1, TAR DNA binding protein 43 (TARDBP), and fused in sarcoma (FUS) genes are the four most common ones. During the last three decades, tremendous effort has been made worldwide to reveal biological pathways underlying the pathogenesis of these gene mutations in ALS/FTD. Accordingly, targeting etiologic genes (i.e., gene therapies) to suppress their toxic effects have been investigated widely. It includes four major strategies: (i) removal or inhibition of abnormal transcribed RNA using microRNA or antisense oligonucleotides (ASOs), (ii) degradation of abnormal mRNA using RNA interference (RNAi), (iii) decrease or inhibition of mutant proteins (e.g., using antibodies against misfolded proteins), and (iv) DNA genome editing with methods such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (CRISPR/Cas). The promising results of these studies have led to the application of some of these strategies into ALS clinical trials, especially for C9orf72 and SOD1. In this paper, we will overview advances in gene therapy in ALS/FTD, focusing on C9orf72, SOD1, TARDBP, and FUS genes.

Keywords: C9orf72; Cu/Zn superoxide dismutase (SOD1); TAR DNA binding protein 43 (TARDBP); amyotrophic lateral sclerosis (ALS); fused in sarcoma (FUS); gene therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of potential strategies in gene therapy for amyotrophic lateral sclerosis. Antisense oligonucleotide (ASO) are short synthetic oligonucleotides (~20 nucleotides). They bind to the targeted mRNA and either (i) induce the mRNA degradation by endogenous RNase H or (ii) block the mRNA translation. This ultimately decreases the expression of certain proteins. In ALS, this strategy has been utilized to reduce the protein level of TDP-43, SOD1 of FUS protein level or to target C9orf72 RNA foci. SiRNAs are double-stranded RNAs that can bind argonaute proteins as part of the RNA-induced silencing complex (RISC), which ultimately leads to the mRNA cleavage. Gene (i.e., either mRNA or cDNA) delivery through viruses (e.g., adeno-associated viral vectors [AAV]) is another option for functional replacement of a missing gene. This approach was utilized in spinal muscular atrophy but needs more investigation in ALS.
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