AUTHOR=Pun Frank W. , Liu Bonnie Hei Man , Long Xi , Leung Hoi Wing , Leung Geoffrey Ho Duen , Mewborne Quinlan T. , Gao Junli , Shneyderman Anastasia , Ozerov Ivan V. , Wang Ju , Ren Feng , Aliper Alexander , Bischof Evelyne , Izumchenko Evgeny , Guan Xiaoming , Zhang Ke , Lu Bai , Rothstein Jeffrey D. , Cudkowicz Merit E. , Zhavoronkov Alex 

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=14

YEAR=2022

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2022.914017

DOI=10.3389/fnagi.2022.914017

ISSN=1663-4365

ABSTRACT=<p>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 (<ext-link ext-link-type="uri" xlink:href="http://als.ai/" xmlns:xlink="http://www.w3.org/1999/xlink">http://als.ai/</ext-link>). Among the proposed targets screened in the c9ALS <italic>Drosophila</italic> model, we verified 8 unreported genes (<italic>KCNB2</italic>, <italic>KCNS3</italic>, <italic>ADRA2B</italic>, <italic>NR3C1</italic>, <italic>P2RY14</italic>, <italic>PPP3CB</italic>, <italic>PTPRC</italic>, and <italic>RARA</italic>) 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.</p>