2. Academic Validation
  3. TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro

TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro

  • BMC Med. 2024 Mar 5;22(1):96. doi: 10.1186/s12916-024-03314-1.
Qing-Qing Duan # 1 2 3,  Han Wang # 4,  Wei-Ming Su 1 2 3,  Xiao-Jing Gu 5,  Xiao-Fei Shen 6,  Zheng Jiang 1 2 3,  Yan-Ling Ren 4,  Bei Cao 1 2 3,  Guo-Bo Li 7,  Yi Wang 8,  Yong-Ping Chen 9 10 11
Affiliations

Affiliations

  • 1 Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2 Institute of Brain Science and Brain-Inspired Technology, West China Hospital, Sichuan University, Sichuan, Chengdu,, 610041, China.
  • 3 Rare Disease Center, West China Hospital, Sichuan University, Sichuan, Chengdu, 610041, China.
  • 4 Department of Pathophysiology, West China College of Basic Medical Sciences and Forensic Medicine, Sichuan University, Sichuan, Chengdu, 610041, China.
  • 5 Mental Health Center, West China Hospital, Sichuan University, Sichuan, Chengdu, 610041, China.
  • 6 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
  • 7 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 8 Department of Pathophysiology, West China College of Basic Medical Sciences and Forensic Medicine, Sichuan University, Sichuan, Chengdu, 610041, China. wangyi83@scu.edu.cn.
  • 9 Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. yongping.chen@wchscu.cn.
  • 10 Institute of Brain Science and Brain-Inspired Technology, West China Hospital, Sichuan University, Sichuan, Chengdu,, 610041, China. yongping.chen@wchscu.cn.
  • 11 Rare Disease Center, West China Hospital, Sichuan University, Sichuan, Chengdu, 610041, China. yongping.chen@wchscu.cn.
  • # Contributed equally.
PMID: 38443977 DOI: 10.1186/s12916-024-03314-1
Abstract

Background: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment.

Methods: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models.

Results: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation.

Conclusions: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.

Keywords

Amyotrophic lateral sclerosis; Drug repurposing; Druggable gene; Mendelian randomization; TBK1.

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