Gene Therapy in Amyotrophic Lateral Sclerosis

被引:41
作者
Fang, Ton [1 ]
Je, Goun [1 ]
Pacut, Peter [1 ]
Keyhanian, Kiandokht [1 ]
Gao, Jeff [1 ]
Ghasemi, Mehdi [1 ]
机构
[1] Univ Massachusetts, Chan Med Sch, Dept Neurol, Worcester, MA 01655 USA
关键词
C9orf72; Cu; Zn superoxide dismutase (SOD1); TAR DNA binding protein 43 (TARDBP); fused in sarcoma (FUS); amyotrophic lateral sclerosis (ALS); gene therapy; FRONTOTEMPORAL LOBAR DEGENERATION; HEXANUCLEOTIDE REPEAT EXPANSION; WILD-TYPE FUS; ANTISENSE OLIGONUCLEOTIDE; ADENOASSOCIATED VIRUS; SUPEROXIDE-DISMUTASE; C9ORF72; EXPANSION; MOUSE MODEL; CLINICAL CHARACTERISTICS; EXTENDS SURVIVAL;
D O I
10.3390/cells11132066
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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页数:21
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