Olfactory neuronal cells as a promising tool to realize the "druggable genome" approach for drug discovery in neuropsychiatric disorders.

Autor:	Mihaljevic M; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Lam M; IMH Neuropsychiatric Genomics Laboratory, Institute of Mental Health, Singapore, Singapore.; Population and Global Health, LKC Medicine, Nanyang Technological University, Singapore, Singapore.; Neurogenomic Biomarkers Laboratory, Zucker Hillside Hospital, Glen Oaks, NY, United States.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States., Ayala-Grosso C; Unit of Cellular Therapy, Centre of Experimental Medicine, Instituto Venezolano de Investigaciones Cientificas IVIC, Caracas, Venezuela., Davis-Batt F; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Schretlen DJ; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Ishizuka K; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Yang K; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States., Sawa A; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States.; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States.; Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States.; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in neuroscience [Front Neurosci] 2023 Mar 10; Vol. 16, pp. 1081124. Date of Electronic Publication: 2023 Mar 10 (Print Publication: 2022).
DOI:	10.3389/fnins.2022.1081124
Abstrakt:	"Druggable genome" is a novel concept that emphasizes the importance of using the information of genome-wide genetic studies for drug discovery and development. Successful precedents of "druggable genome" have recently emerged for some disorders by combining genomic and gene expression profiles with medical and pharmacological knowledge. One of the key premises for the success is the good access to disease-relevant tissues from "living" patients in which we may observe molecular expression changes in association with symptomatic alteration. Thus, given brain biopsies are ethically and practically difficult, the application of the "druggable genome" approach is challenging for neuropsychiatric disorders. Here, to fill this gap, we propose the use of olfactory neuronal cells (ONCs) biopsied and established via nasal biopsy from living subjects. By using candidate genes that were proposed in a study in which genetic information, postmortem brain expression profiles, and pharmacological knowledge were considered for cognition in the general population, we addressed the utility of ONCs in the "druggable genome" approach by using the clinical and cell resources of an established psychosis cohort in our group. Through this pilot effort, we underscored the chloride voltage-gated channel 2 (CLCN2) gene as a possible druggable candidate for early-stage psychosis. The CLCN2 gene expression was associated with verbal memory, but not with other dimensions in cognition, nor psychiatric manifestations (positive and negative symptoms). The association between this candidate molecule and verbal memory was also confirmed at the protein level. By using ONCs from living subjects, we now provide more specific information regarding molecular expression and clinical phenotypes. The use of ONCs also provides the opportunity of validating the relationship not only at the RNA level but also protein level, leading to the potential of functional assays in the future. Taken together, we now provide evidence that supports the utility of ONCs as a tool for the "druggable genome" approach in translational psychiatry. Competing Interests: Under an agreement with Psychological Assessment Resources, Inc., DS is entitled to a share of royalty on sales of a test used in the study described in this article. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Mihaljevic, Lam, Ayala-Grosso, Davis-Batt, Schretlen, Ishizuka, Yang and Sawa.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu