Identification of Therapeutic Targets for Amyotrophic Lateral Sclerosis Using PandaOmics - An AI-Enabled Biological Target Discovery Platform

被引：54

作者：

Pun, Frank W. ^{[1
]}

Liu, Bonnie Hei Man ^{[1
]}

Long, Xi ^{[1
]}

Leung, Hoi Wing ^{[1
]}

Leung, Geoffrey Ho Duen ^{[1
]}

Mewborne, Quinlan T. ^{[2
]}

Gao, Junli ^{[2
]}

Shneyderman, Anastasia ^{[1
]}

Ozerov, Ivan V. ^{[1
]}

Wang, Ju ^{[1
]}

Ren, Feng ^{[1
]}

Aliper, Alexander ^{[1
]}

Bischof, Evelyne ^{[3
,4
]}

Izumchenko, Evgeny ^{[5
]}

Guan, Xiaoming ^{[6
]}

Zhang, Ke ^{[2
,7
]}

Lu, Bai ^{[8
]}

Rothstein, Jeffrey D. ^{[9
,10
]}

Cudkowicz, Merit E. ^{[11
]}

Zhavoronkov, Alex ^{[1
,12
]}

机构：

[1] Insilico Med Hong Kong Ltd, Hong Kong Sci & Technol Pk, Hong Kong, Peoples R China

[2] Mayo Clin Florida, Dept Neurosci, Jacksonville, FL USA

[3] Shanghai Univ Med & Hlth Sci, Coll Clin Med, Shanghai, Peoples R China

[4] Univ Zurich, Int Ctr Multimorbid & Complex Med ICMC, Zurich, Switzerland

[5] Univ Chicago, Dept Med, Sect Hematol & Oncol, Chicago, IL USA

[6] 4B Technol Ltd, Suzhou, Peoples R China

[7] Mayo Clin, Neurosci Grad Program, Grad Sch Biomed Sci, Jacksonville, FL USA

[8] Tsinghua Univ, McGovern Inst Brain Res, Sch Pharmaceut Sci, IDG, Beijing, Peoples R China

[9] Johns Hopkins Univ, Brain Sci Inst, Sch Med, Baltimore, MD USA

[10] Johns Hopkins Univ, Dept Neurol, Sch Med, Baltimore, MD USA

[11] Harvard Med Sch, Massachusetts Gen Hosp, Healey & AMG Ctr ALS, Boston, MA 02115 USA

[12] Buck Inst Res Aging, Novato, CA 94945 USA

来源：

FRONTIERS IN AGING NEUROSCIENCE | 2022年 / 14卷

关键词：

target novelty; artificial intelligence; time machine; multi-omics; FIBROBLAST GROWTH-FACTORS; NEURONAL CELL-DEATH; MOTOR-NEURONS; HEXANUCLEOTIDE REPEAT; ANALYSES IDENTIFY; OXIDATIVE STRESS; GENE-EXPRESSION; UNITED-STATES; MOUSE MODEL; ALS;

D O I：

10.3389/fnagi.2022.914017

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with ill-defined pathogenesis, calling for urgent developments of new therapeutic regimens. Herein, we applied PandaOmics, an AI-driven target discovery platform, to analyze the expression profiles of central nervous system (CNS) samples (237 cases; 91 controls) from public datasets, and direct iPSC-derived motor neurons (diMNs) (135 cases; 31 controls) from Answer ALS. Seventeen high-confidence and eleven novel therapeutic targets were identified and will be released onto ALS.AI (). Among the proposed targets screened in the c9ALS Drosophila model, we verified 8 unreported genes (KCNB2, KCNS3, ADRA2B, NR3C1, P2RY14, PPP3CB, PTPRC, and RARA) whose suppression strongly rescues eye neurodegeneration. Dysregulated pathways identified from CNS and diMN data characterize different stages of disease development. Altogether, our study provides new insights into ALS pathophysiology and demonstrates how AI speeds up the target discovery process, and opens up new opportunities for therapeutic interventions.

引用

页数：16

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