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Translating Atherosclerosis Research from Bench to Bedside: Navigating the Barriers for Effective Preclinical Drug Discovery

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Journal Clin Sci (Lond)
Date 2022 Dec 2
PMID 36459456
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Abstract

Cardiovascular disease (CVD) remains the leading cause of death worldwide. An ongoing challenge remains the development of novel pharmacotherapies to treat CVD, particularly atherosclerosis. Effective mechanism-informed development and translation of new drugs requires a deep understanding of the known and currently unknown biological mechanisms underpinning atherosclerosis, accompanied by optimization of traditional drug discovery approaches. Current animal models do not precisely recapitulate the pathobiology underpinning human CVD. Accordingly, a fundamental limitation in early-stage drug discovery has been the lack of consensus regarding an appropriate experimental in vivo model that can mimic human atherosclerosis. However, when coupled with a clear understanding of the specific advantages and limitations of the model employed, preclinical animal models remain a crucial component for evaluating pharmacological interventions. Within this perspective, we will provide an overview of the mechanisms and modalities of atherosclerotic drugs, including those in the preclinical and early clinical development stage. Additionally, we highlight recent preclinical models that have improved our understanding of atherosclerosis and associated clinical consequences and propose model adaptations to facilitate the development of new and effective treatments.

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References
1.
Fan J, Kitajima S, Watanabe T, Xu J, Zhang J, Liu E . Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacol Ther. 2014; 146:104-19. PMC: 4304984. DOI: 10.1016/j.pharmthera.2014.09.009. View

2.
Chew P, Yuen D, Stefanovic N, Pete J, Coughlan M, Jandeleit-Dahm K . Antiatherosclerotic and renoprotective effects of ebselen in the diabetic apolipoprotein E/GPx1-double knockout mouse. Diabetes. 2010; 59(12):3198-207. PMC: 2992783. DOI: 10.2337/db10-0195. View

3.
Ray K, Wright R, Kallend D, Koenig W, Leiter L, Raal F . Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020; 382(16):1507-1519. DOI: 10.1056/NEJMoa1912387. View

4.
Omori H, Ota H, Hara M, Kawase Y, Tanigaki T, Hirata T . Effect of PCSK-9 Inhibitors on Lipid-Rich Vulnerable Coronary Plaque Assessed by Near-Infrared Spectroscopy. JACC Cardiovasc Imaging. 2020; 13(7):1639-1641. DOI: 10.1016/j.jcmg.2020.02.019. View

5.
Peled M, Nishi H, Weinstock A, Barrett T, Zhou F, Quezada A . A wild-type mouse-based model for the regression of inflammation in atherosclerosis. PLoS One. 2017; 12(3):e0173975. PMC: 5349694. DOI: 10.1371/journal.pone.0173975. View