Translating atherosclerosis research from bench to bedside: navigating the barriers for effective preclinical drug discovery

doi:10.1042/CS20210862

. 2022 Dec 9;136(23):1731-1758.

doi: 10.1042/CS20210862.

Translating atherosclerosis research from bench to bedside: navigating the barriers for effective preclinical drug discovery

Lauren T May^#¹, Belinda A Bartolo^#², David G Harrison³, Tomasz Guzik^{4

5}, Grant R Drummond⁶, Gemma A Figtree^{7

8}, Rebecca H Ritchie⁹, Kerry-Anne Rye¹⁰, Judy B de Haan^{11

12

13

14

15}

Affiliations

¹ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
² Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
³ Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A.
⁴ Institute of Cardiovascular and Medical Sciences, University of Glasgow, U.K.
⁵ Department of Medicine, Jagiellonian University Medical College, Krakow, Poland.
⁶ Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Melbourne, Victoria, Australia.
⁷ Kolling Research Institute, University of Sydney, Sydney, Australia.
⁸ Imaging and Phenotyping Laboratory, Charles Perkins Centre and Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
⁹ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
¹⁰ Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia.
¹¹ Cardiovascular Inflammation and Redox Biology Lab, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
¹² Department of Chemistry and Biotechnology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.
¹³ Department Cardiometabolic Health, University of Melbourne, Parkville, Victoria 3010, Australia.
¹⁴ Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria 3086, Australia.
¹⁵ Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia.

^# Contributed equally.

PMID: 36459456
PMCID: PMC9727216
DOI: 10.1042/CS20210862

Translating atherosclerosis research from bench to bedside: navigating the barriers for effective preclinical drug discovery

Lauren T May et al. Clin Sci (Lond). 2022.

. 2022 Dec 9;136(23):1731-1758.

doi: 10.1042/CS20210862.

Authors

Affiliations

¹ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
² Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
³ Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A.
⁴ Institute of Cardiovascular and Medical Sciences, University of Glasgow, U.K.
⁵ Department of Medicine, Jagiellonian University Medical College, Krakow, Poland.
⁶ Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Melbourne, Victoria, Australia.
⁷ Kolling Research Institute, University of Sydney, Sydney, Australia.
⁸ Imaging and Phenotyping Laboratory, Charles Perkins Centre and Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
⁹ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
¹⁰ Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia.
¹¹ Cardiovascular Inflammation and Redox Biology Lab, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
¹² Department of Chemistry and Biotechnology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.
¹³ Department Cardiometabolic Health, University of Melbourne, Parkville, Victoria 3010, Australia.
¹⁴ Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria 3086, Australia.
¹⁵ Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia.

^# Contributed equally.

PMID: 36459456
PMCID: PMC9727216
DOI: 10.1042/CS20210862

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.

Keywords: atherosclerosis; cardiovascular disease; coronary artery disease; drug discovery and design; model organisms.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

**Figure 1. Multiple therapeutic targets exist for the treatment of atherosclerosis**
(1) Statins reduce LDL-C production by inhibiting HMG-CoA reductase; (2) PCSK9 inhibitors disrupt the recycling of LDLR; (3) PCSK9 gene therapy can be used to treat patients with familial hypercholesterolemia (FH); (4) PPAR agonists promote expression of lipid metabolism genes; (5) LXR agonists promote expression of lipid and bile acid metabolism genes and increase reverse cholesterol transport; (6) ANGPTL3 inhibitors counteract LPL inhibition and reduce TG-rich lipoprotein (TRL) levels; (7) ApoC3 inhibition increases LPL activation and decreases TG levels; (8) Bempedoic acid catalyses the production of acetyl-CoA, and decreases HMG-CoA formation; (9) Lp(a) inhibitors reduce LDL-C levels.

**Figure 2. Timeline of the translation of PCSK9 inhibitors from discovery to Federal Drug Administration (FDA) approval**

See this image and copyright information in PMC

References

1. Birger M., Kaldjian A.S., Roth G.A., Moran A.E., Dieleman J.L. and Bellows B.K. (2021) Spending on cardiovascular disease and cardiovascular risk factors in the United States: 1996 to 2016. Circulation 144, 271–282 10.1161/CIRCULATIONAHA.120.053216 - DOI - PMC - PubMed
1. Figtree G.A., Vernon S.T., Hadziosmanovic N., Sundstrom J., Alfredsson J., Arnott C.et al. . (2021) Mortality in STEMI patients without standard modifiable risk factors: a sex-disaggregated analysis of SWEDEHEART registry data. Lancet 397, 1085–1094 10.1016/S0140-6736(21)00272-5 - DOI - PubMed
1. Waters D.D., Brotons C., Chiang C.W., Ferrieres J., Foody J., Jukema J.W.et al. . (2009) Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation 120, 28–34 10.1161/CIRCULATIONAHA.108.838466 - DOI - PubMed
1. Engelen S.E., Robinson A.J.B., Zurke Y.X. and Monaco C. (2022) Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed? Nat. Rev. Cardiol. 10.1038/s41569-021-00668-4 - DOI - PMC - PubMed
1. Figtree G.A., Broadfoot K., Casadei B., Califf R., Crea F., Drummond G.R.et al. . (2021) A call to action for new global approaches to cardiovascular disease drug solutions. Eur. Heart J. 42, 1464–1475 10.1093/eurheartj/ehab068 - DOI - PubMed

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[1] Birger M., Kaldjian A.S., Roth G.A., Moran A.E., Dieleman J.L. and Bellows B.K. (2021) Spending on cardiovascular disease and cardiovascular risk factors in the United States: 1996 to 2016. Circulation 144, 271–282 10.1161/CIRCULATIONAHA.120.053216 - DOI - PMC - PubMed

[2] Birger M., Kaldjian A.S., Roth G.A., Moran A.E., Dieleman J.L. and Bellows B.K. (2021) Spending on cardiovascular disease and cardiovascular risk factors in the United States: 1996 to 2016. Circulation 144, 271–282 10.1161/CIRCULATIONAHA.120.053216 - DOI - PMC - PubMed

[3] Figtree G.A., Vernon S.T., Hadziosmanovic N., Sundstrom J., Alfredsson J., Arnott C.et al. . (2021) Mortality in STEMI patients without standard modifiable risk factors: a sex-disaggregated analysis of SWEDEHEART registry data. Lancet 397, 1085–1094 10.1016/S0140-6736(21)00272-5 - DOI - PubMed

[4] Figtree G.A., Vernon S.T., Hadziosmanovic N., Sundstrom J., Alfredsson J., Arnott C.et al. . (2021) Mortality in STEMI patients without standard modifiable risk factors: a sex-disaggregated analysis of SWEDEHEART registry data. Lancet 397, 1085–1094 10.1016/S0140-6736(21)00272-5 - DOI - PubMed

[5] Waters D.D., Brotons C., Chiang C.W., Ferrieres J., Foody J., Jukema J.W.et al. . (2009) Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation 120, 28–34 10.1161/CIRCULATIONAHA.108.838466 - DOI - PubMed

[6] Waters D.D., Brotons C., Chiang C.W., Ferrieres J., Foody J., Jukema J.W.et al. . (2009) Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation 120, 28–34 10.1161/CIRCULATIONAHA.108.838466 - DOI - PubMed

[7] Engelen S.E., Robinson A.J.B., Zurke Y.X. and Monaco C. (2022) Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed? Nat. Rev. Cardiol. 10.1038/s41569-021-00668-4 - DOI - PMC - PubMed

[8] Engelen S.E., Robinson A.J.B., Zurke Y.X. and Monaco C. (2022) Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed? Nat. Rev. Cardiol. 10.1038/s41569-021-00668-4 - DOI - PMC - PubMed

[9] Figtree G.A., Broadfoot K., Casadei B., Califf R., Crea F., Drummond G.R.et al. . (2021) A call to action for new global approaches to cardiovascular disease drug solutions. Eur. Heart J. 42, 1464–1475 10.1093/eurheartj/ehab068 - DOI - PubMed

[10] Figtree G.A., Broadfoot K., Casadei B., Califf R., Crea F., Drummond G.R.et al. . (2021) A call to action for new global approaches to cardiovascular disease drug solutions. Eur. Heart J. 42, 1464–1475 10.1093/eurheartj/ehab068 - DOI - PubMed

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Translating atherosclerosis research from bench to bedside: navigating the barriers for effective preclinical drug discovery

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Translating atherosclerosis research from bench to bedside: navigating the barriers for effective preclinical drug discovery

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