Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons in the brain and spinal cord. The causes of ALS are not fully understood. About 10% of ALS cases were associated with genetic factors. Since the discovery of the first familial ALS pathogenic gene SOD1 in 1993 and with the technology advancement, now over 40 ALS genes have been found. Recent studies have identified ALS related genes including ANXA11, ARPP21, CAV1, C21ORF2, CCNF, DNAJC7, GLT8D1, KIF5A, NEK1, SPTLC1, TIA1, and WDR7. These genetic discoveries contribute to a better understanding of ALS and show the potential to aid the development of better ALS treatments. Besides, several genes appear to be associated with other neurological disorders, such as CCNF and ANXA11 linked to FTD. With the deepening understanding of the classic ALS genes, rapid progress has been made in gene therapies. In this review, we summarize the latest progress on classical ALS genes and clinical trials for these gene therapies, as well as recent findings on newly discovered ALS genes.

Keywords: amyotrophic lateral sclerosis; antisense oligonucleotide; gene therapy; genetics; motoneuron disease; neurogenetics.

Figure 1

ALS Gene Discovery from 1990 to 2022. The cumulative number of ALS-related genes discovered is growing rapidly. ALS-related genes are plotted and their respective inheritance patterns are represented by different colored circles.

Figure 2

Methods for the discovery of ALS pathogenic genes and their association with other neurological diseases. Each circle indicates one disease and its name is presented beside it in red color. There are 15 genes associated with both ALS and FTD; 1 gene associated with ALS, ataxia, and FTD; 1 gene associated with both ALS and SCA2; 1 gene associated with both ALS and HSP; 1 gene associated with ALS, HSP, and CMT2. ALS, amyotrophic lateral sclerosis; GWAS, genome-wide association study; WGS, whole-genome sequencing; WES, whole-exome sequencing; NGS, next-generation sequencing; RP-PCR, repeat-primed polymerase chain reaction; SNP, single nucleotide polymorphism.