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The Role of Genetics in Advancing Cardiometabolic Drug Development

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Abstract

Purpose of Review

The objective of this review is to explore the role of genetics in cardiometabolic drug development. The declining costs of sequencing and the availability of large-scale genomic data have deepened our understanding of cardiometabolic diseases, revolutionizing drug discovery and development methodologies. We highlight four key areas in which genetics is empowering drug development for cardiometabolic disease: (1) identifying drug candidates, (2) anticipating drug target failures, (3) silencing and editing genes, and (4) enriching clinical trials.

Recent Findings

Identifying novel drug targets through genetic discovery studies and the use of genetic variants as indicators of potential drug efficacy and safety have become critical components of cardiometabolic drug discovery. We highlight the successes of genetically-informed therapeutic strategies, such as PCSK9 and ANGPTL3 inhibitors in lipid lowering and the emerging role of polygenic risk scores in improving the efficiency of clinical trials. Additionally, we explore the potential of gene silencing and editing technologies, such as antisense oligonucleotides and small interfering RNA, showcasing their promise in addressing diseases refractory to conventional treatments.

Summary

In this review, we highlight four use cases that demonstrate the vital role of genetics in cardiometabolic drug development: (1) identifying drug candidates, (2) anticipating drug target failures, (3) silencing and editing genes, and (4) enriching clinical trials. Through these advances, genetics has paved the way to increased efficiency of drug development as well as the discovery of more personalized and effective treatments for cardiometabolic disease.

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Data Availability

No datasets were generated or analyzed during the current study

Change history

  • 16 March 2024

    The original version of this paper was updated to correct the word "hinformed" to "informed".

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Funding

Dr. Fahed receives funding from the National Heart Lung and Blood Institute under award numbers K08 HL161448 and R01 HL164629.

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Authors and Affiliations

  1. Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street|CPZN 3.128, Boston, MA, 02114, USA

    Roukoz Abou-Karam, Fangzhou Cheng, Shoshana Gady & Akl C. Fahed

  2. Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Roukoz Abou-Karam, Fangzhou Cheng, Shoshana Gady & Akl C. Fahed

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  1. Roukoz Abou-Karam
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R.A.K. conceptualized the scope of the review, led the literature review process, synthesized findings, and drafted the manuscript. F.C. and S.G. participated in gathering and analyzing relevant literature and assisted in revising the manuscript. A.C.F. supervised the literature review and writing of the manuscript. All authors approved the final version to be published and agree to be accountable for all aspects of the work.

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Correspondence to Akl C. Fahed.

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Dr. Fahed reports being a co-founder of Goodpath. Dr. Abou-Karam receives consulting fees from Goodpath. The other authors have no disclosures to report.

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Abou-Karam, R., Cheng, F., Gady, S. et al. The Role of Genetics in Advancing Cardiometabolic Drug Development. Curr Atheroscler Rep (2024). https://doi.org/10.1007/s11883-024-01195-6

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