OmicSynth: an open multi‐omic community resource for identifying druggable targets across neurodegenerative diseases

Abstract

AbstractBackgroundWhile there have been recent successes for Alzheimer’s disease (AD) therapeutics, successful disease‐modifying treatments for AD and neurodegenerative disorders (NDD) remain rare, highlighting the importance of a mechanistic approach in creating therapies. There is an urgent need for disease‐modifying therapeutics, as the World Health Organization estimates dementia diagnosis to reach 78 million by 2030. Ultimately, in the absence of disease‐modifying therapies, the devastating health, social, and economic impacts of dementia and related NDDs will be catastrophic. Here, we generate new understandings on the basis of six NDDs, including AD, and to identify rational therapeutic targets that are genetically backed.MethodWe utilized six NDD specific genome wide association studies (GWAS) ‐ AD, amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), Parkinson’s disease (PD), and Progressive supranuclear palsy (PSP) ‐ and multi‐omic data sets to perform Summary‐data‐based Mendelian Randomization (SMR) to identify genetic targets. We created a therapeutic scheme to classify identified target genes into strata based on known druggability and approved therapeutics for enabling drug discovery and repurposing. We prioritized identified genes as therapeutic targets of interest into three categories: “novel”, “known”, and “difficult”. In parallel, we provide mechanistic insights into disease processes and potential network‐level consequences of gene‐based therapeutics.ResultWe identified 116 AD, 3 ALS, 5 LBD, 46 PD, and 9 PSP target genes passing multiple test corrections (pSMR_multi < 2.95E‐06 and pHEIDI > 0.01) of which 15 were significant in more than two NDDs. Identified target genes were then classified into 41 novel targets, 3 known targets, and 115 difficult targets ‐ corresponding to our therapeutic scheme. Overall, we found four significant target genes in AD and PD, APOC4, LRRC37A2, MMRN1, and ZNF646, and one gene in companion gene networks in ALS, OXT, to present potential liver toxicity issues.ConclusionOur findings and a therapeutic scheme nominate 41 novel targets as promising for drug discovery and repurposing. In particular, KAT8 and KCNN4 present as promising gene targets for further drug development and repurposing. Existing therapeutic compounds, MG149 and Riluzole, target them both genes and have been successfully used in reducing NDD‐related symptomatology.