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TBK1, a Novel Drug Repurposing Target for Amyotrophic Lateral Sclerosis: Evidence from Druggable Genome Mendelian Randomization and Pharmacological Verification in Vitro
30 Pages Posted: 19 Jun 2023
More...Abstract
Background: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS), therefore, drug repurposing may provide a rapid approach to meet the urgent need for treatment.Object and
Methods: To identify therapeutic targets associated with ALS, firstly, we conducted a mendelian randomization (MR) analysis based on large-scale public data and a drug repurposing analysis. Then, two FDA-approval drugs, Amlexanox (AMX) and Fostamatinib (R788), were chosen to assess the efficacy and safety in ALS cell models presenting overly activated TBK1 phosphorylation.
Results: MR analysis yielded TNFSF13, CD68, TNFSF12, TBK1, RESP18, GDF9, PTPRN and GPX3 as potential ALS drugs target genes, of which TBK1, TNFSF12, RESP18, PTPRN and GPX3 were again validated in the colocalization analysis. Among them, the expression levels of TBK1 and TNFSF12 were found to increase in patients’ blood, while upregulation of RESP18 and downregulation of PTPRN were seen in brain. GPX3 displayed opposite expression traits in these two samples. Actionable drug target genes analysis obtained five drugs with repurposing opportunities acting on three drug-modified gene targets, including TBK1, TNFSF12, and GPX3. Further pharmacological analysis revealed that AMX and R788 both inhibited cGAS/STING signaling elicited by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1) via blocking TBK1 phosphorylation, leading to ameliorated neural cell inflammation.
Conclusion: Our findings provided genetic evidence supporting TBK1, TNFSF12, RESP18, PTPRN and GPX3 served as promising ALS therapeutic targets, while prioritized repurposing uses for AMX and R788 in treating ALS featured by over-activated cGAS/STING signaling via inhibiting TBK1 phosphorylation.
Funding: This study was supported by the National Key Research and Development Program of China (Grant no. 2022YFC2703101 to Y.P.C.), the Science and Technology Bureau Fund of Sichuan Province (Grant no. 2021YFS0051 to Y.W and Grant no. 2023YFS0269 to Y.P.C.), the National Natural Science Fund of China (Grant No. 81971188 to Y.P.C.), the National Natural Science Fund of Sichuan (Grant no. 2022NSFSC0749 to B.C.), and the 1·3·5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University (Grant No. 2023HXFH032 to Y.P.C.).
Declaration of Interest: The authors declare that there is no conflict of interest.
Keywords: Amyotrophic lateral sclerosis, Mendelian randomization, drug repurposing, druggable gene, TBK1
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