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Current Atherosclerosis Reports

07-03-2024 | Review

The Role of Genetics in Advancing Cardiometabolic Drug Development

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

Published in: Current Atherosclerosis Reports

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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.
Literature
1.
Tsao CW, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, et al. Heart disease and stroke statistics—2023 update: a report from the American Heart Association. Circulation. 2023;147:e93-621.PubMedCrossRef
2.
Mensah GA, Roth GA, Fuster V. The global burden of cardiovascular diseases and risk factors. J Am Coll Cardiol. 2019;74:2529–32.PubMedCrossRef
3.
Zhou W, Kanai M, Wu K-HH, Rasheed H, Tsuo K, Hirbo JB, et al. Global Biobank Meta-analysis Initiative: powering genetic discovery across human disease. Cell Genomics. 2022;2:100192.PubMedPubMedCentralCrossRef
4.
The “All of Us” research program. N Engl J Med. 2019;381:668–76.
5.
Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562:203–9.PubMedPubMedCentralCrossRef
6.
Wouters OJ, McKee M, Luyten J. Estimated research and development investment Needed to Bring a New Medicine to Market, 2009–2018. JAMA. 2020;323:844–53.PubMedPubMedCentralCrossRef
7.
Schuhmacher A, Hinder M, Von Stegmann Und Stein A, Hartl D, Gassmann O. Analysis of pharma R&D productivity – a new perspective needed. Drug Discov Today. 2023;28:103726.PubMedCrossRef
8.
Moore TJ, Zhang H, Anderson G, Alexander GC. Estimated costs of pivotal trials for novel therapeutic agents approved by the US Food and Drug Administration, 2015–2016. JAMA Intern Med. 2018;178:1451–7.PubMedPubMedCentralCrossRef
9.
10.
Arrowsmith J, Miller P. Trial watch: phase II and phase III attrition rates 2011–2012. Nat Rev Drug Discov. 2013;12:569.PubMedCrossRef
11.
El Khoury P, Elbitar S, Ghaleb Y, Khalil YA, Varret M, Boileau C, et al. PCSK9 mutations in familial hypercholesterolemia: from a groundbreaking discovery to anti-PCSK9 therapies. Curr Atheroscler Rep. 2017;19:49.PubMedCrossRef
12.
• Trajanoska K, Bhérer C, Taliun D, Zhou S, Richards JB, Mooser V. From target discovery to clinical drug development with human genetics. Nature. 2023;620:737–45. This review paper details the process of translating genetic discoveries into clinical drug development.PubMedCrossRef
13.
Nelson MR, Tipney H, Painter JL, Shen J, Nicoletti P, Shen Y, et al. The support of human genetic evidence for approved drug indications. Nat Genet. 2015;47:856–60.PubMedCrossRef
14.
King EA, Davis JW, Degner JF. Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. PLOS Genet. 2019;15:e1008489.PubMedPubMedCentralCrossRef
15.
Abifadel M, Varret M, Rabès J-P, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6.PubMedCrossRef
16.
Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010;363:2220–7.PubMedPubMedCentralCrossRef
17.
18.
•• Carss KJ, Deaton AM, Del Rio-Espinola A, Diogo D, Fielden M, Kulkarni DA, et al. Using human genetics to improve safety assessment of therapeutics. Nat Rev Drug Discov. 2023;22:145–62. This review paper highlights the role of human genetics in enhancing the safety assessment of therapeutics, which is pivotal in advancing the development of drugs that are both effective and safe.PubMedCrossRef
19.
20.
• Nissen SE, Linnebjerg H, Shen X, Wolski K, Ma X, Lim S, et al. Lepodisiran, an extended-duration short interfering RNA targeting lipoprotein(a): a randomized dose-ascending clinical trial. JAMA [Internet]. 2023 [cited 2023 Nov 26]; Available from: https://​doi.​org/​10.​1001/​jama.​2023.​21835. Findings from this study offer critical insights into the efficacy of extended-duration RNA interference therapies in targeting lipoprotein(a) paving the way for novel therapeutic approaches in the cardiometabolic field.
21.
22.
•• Fahed AC, Philippakis AA, Khera AV. The potential of polygenic scores to improve cost and efficiency of clinical trials. Nat Commun. 2022;13:1–4. This article demonstrates the potential of polygenic scores in enhancing the cost-efficiency and effectiveness of clinical trials.CrossRef
23.
24.
25.
Alcalai R, Seidman JG, Seidman CE. Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics. J Cardiovasc Electrophysiol. 2008;19:104–10.PubMedCrossRef
26.
27.
28.
Bergström A, McCarthy SA, Hui R, Almarri MA, Ayub Q, Danecek P, et al. Insights into human genetic variation and population history from 929 diverse genomes. Science. 2020;367:eaay5012.PubMedPubMedCentralCrossRef
29.
Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, et al. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med. 2020;383:711–20.PubMedCrossRef
30.
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–22.PubMedCrossRef
31.
Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–107.PubMedCrossRef
32.
Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999–1006.PubMedCrossRef
33.
34.
Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396:759–69.PubMedCrossRef
35.
Baxter SM, Posey JE, Lake NJ, Sobreira N, Chong JX, Buyske S, et al. Centers for Mendelian Genomics: a decade of facilitating gene discovery. Genet Med. 2022;24:784–97.PubMedPubMedCentralCrossRef
36.
Posey JE, O’Donnell-Luria AH, Chong JX, Harel T, Jhangiani SN, Coban Akdemir ZH, et al. Insights into genetics, human biology and disease gleaned from family based genomic studies. Genet Med. 2019;21:798–812.PubMedPubMedCentralCrossRef
37.
Aragam KG, Jiang T, Goel A, Kanoni S, Wolford BN, Atri DS, et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat Genet. 2022;54:1803–15.PubMedPubMedCentralCrossRef
38.
Graham SE, Clarke SL, Wu K-HH, Kanoni S, Zajac GJM, Ramdas S, et al. The power of genetic diversity in genome-wide association studies of lipids. Nature. 2021;600:675–9.PubMedPubMedCentralCrossRef
39.
Evangelou E, Warren HR, Mosen-Ansorena D, Mifsud B, Pazoki R, Gao H, et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat Genet. 2018;50:1412–25.PubMedPubMedCentralCrossRef
40.
Mahajan A, Spracklen CN, Zhang W, Ng MCY, Petty LE, Kitajima H, et al. Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. Nat Genet. 2022;54:560–72.PubMedPubMedCentralCrossRef
41.
Mizoguchi T, MacDonald BT, Bhandary B, Popp NR, Laprise D, Arduini A, et al. Coronary disease association with ADAMTS7 is due to protease activity. Circ Res. 2021;129:458–70.PubMedPubMedCentralCrossRef
42.
Nasser J, Bergman DT, Fulco CP, Guckelberger P, Doughty BR, Patwardhan TA, et al. Genome-wide enhancer maps link risk variants to disease genes. Nature. 2021;593:238–43.PubMedPubMedCentralCrossRef
43.
Weeks EM, Ulirsch JC, Cheng NY, Trippe BL, Fine RS, Miao J, et al. Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases. Nat Genet. 2023;55:1267–76.PubMedPubMedCentralCrossRef
44.
Yu F, Cato LD, Weng C, Liggett LA, Jeon S, Xu K, et al. Variant to function mapping at single-cell resolution through network propagation. Nat Biotechnol. 2022;40:1644–53.PubMedPubMedCentralCrossRef
45.
Minikel EV, Karczewski KJ, Martin HC, Cummings BB, Whiffin N, Rhodes D, et al. Evaluating drug targets through human loss-of-function genetic variation. Nature. 2020;581:459–64.PubMedPubMedCentralCrossRef
46.
Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 2017;544:235–9.PubMedPubMedCentralCrossRef
47.
48.
Emdin CA, Khera AV, Chaffin M, Klarin D, Natarajan P, Aragam K, et al. Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. Nat Commun. 2018;9:1613.PubMedPubMedCentralCrossRef
49.
Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32:40–51.PubMedCrossRef
50.
Pammolli F, Magazzini L, Riccaboni M. The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov. 2011;10:428–38.PubMedCrossRef
51.
Scannell JW, Blanckley A, Boldon H, Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov. 2012;11:191–200.PubMedCrossRef
52.
Plenge RM, Scolnick EM, Altshuler D. Validating therapeutic targets through human genetics. Nat Rev Drug Discov. 2013;12:581–94.PubMedCrossRef
53.
Holmes MV, Ala-Korpela M, Smith GD. Mendelian randomization in cardiometabolic disease: challenges in evaluating causality. Nat Rev Cardiol. 2017;14:577–90.PubMedPubMedCentralCrossRef
54.
Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45:1345–52.PubMedPubMedCentralCrossRef
55.
Frikke-Schmidt R, Nordestgaard BG, Stene MCA, Sethi AA, Remaley AT, Schnohr P, et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA. 2008;299:2524–32.PubMedCrossRef
56.
Armitage J, Holmes MV, Preiss D. Cholesteryl Ester Transfer Protein Inhibition for Preventing Cardiovascular Events. J Am Coll Cardiol. 2019;73:477–87.PubMedPubMedCentralCrossRef
57.
AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.CrossRef
58.
Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–99.PubMedCrossRef
59.
Ference BA, Ray KK, Catapano AL, Ference TB, Burgess S, Neff DR, et al. Mendelian randomization study of ACLY and cardiovascular disease. N Engl J Med. 2019;380:1033–42.PubMedPubMedCentralCrossRef
60.
Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380:1022–32.PubMedCrossRef
61.
Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJP, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388:1353–64.PubMedCrossRef
62.
Diogo D, Tian C, Franklin CS, Alanne-Kinnunen M, March M, Spencer CCA, et al. Phenome-wide association studies across large population cohorts support drug target validation. Nat Commun. 2018;9:4285.PubMedPubMedCentralCrossRef
63.
Diogo D, Bastarache L, Liao KP, Graham RR, Fulton RS, Greenberg JD, et al. TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits. PLoS ONE. 2015;10:e0122271.PubMedPubMedCentralCrossRef
64.
The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet. 2012;379:1214–24.
65.
66.
67.
Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382:1507–19.PubMedCrossRef
68.
O’Donoghue ML, Rosenson RS, Gencer B, López JAG, Lepor NE, Baum SJ, et al. Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. N Engl J Med. 2022;387:1855–64.PubMedCrossRef
69.
Yeang C, Karwatowska-Prokopczuk E, Su F, Dinh B, Xia S, Witztum JL, et al. Effect of pelacarsen on lipoprotein(a) cholesterol and corrected low-density lipoprotein cholesterol. J Am Coll Cardiol. 2022;79:1035–46.PubMedCrossRef
70.
Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379:22–31.PubMedCrossRef
71.
72.
73.
74.
Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia. Proc Natl Acad Sci. 2008;105:1620–5.PubMedPubMedCentralCrossRef
75.
Menzel S, Garner C, Gut I, Matsuda F, Yamaguchi M, Heath S, et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet. 2007;39:1197–9.PubMedCrossRef
76.
Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008;322:1839–42.PubMedCrossRef
77.
Lettre G, Sankaran VG, Bezerra MAC, Araújo AS, Uda M, Sanna S, et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and β-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci. 2008;105:11869–74.PubMedPubMedCentralCrossRef
78.
Frangoul H, Altshuler D, Cappellini MD, Chen Y-S, Domm J, Eustace BK, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med. 2021;384:252–60.PubMedCrossRef
79.
Marston NA, Kamanu FK, Nordio F, Gurmu Y, Roselli C, Sever PS, et al. Predicting benefit from evolocumab therapy in patients with atherosclerotic disease using a genetic risk score: results from the FOURIER Trial. Circulation. 2020;141:616–23.PubMedCrossRef
80.
Damask A, Steg PG, Schwartz GG, Szarek M, Hagström E, Badimon L, et al. Patients with high genome-wide polygenic risk scores for coronary artery disease may receive greater clinical benefit from alirocumab treatment in the ODYSSEY OUTCOMES trial. Circulation. 2020;141:624–36.PubMedCrossRef
81.
Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.PubMedCrossRef
82.
83.
Klarin D, Natarajan P. Clinical utility of polygenic risk scores for coronary artery disease. Nat Rev Cardiol. 2022;19:291–301.PubMedCrossRef
84.
85.
86.
Pallmann P, Bedding AW, Choodari-Oskooei B, Dimairo M, Flight L, Hampson LV, et al. Adaptive designs in clinical trials: why use them, and how to run and report them. BMC Med. 2018;16:29.PubMedPubMedCentralCrossRef
Metadata
Title
The Role of Genetics in Advancing Cardiometabolic Drug Development
Authors
Roukoz Abou-Karam
Fangzhou Cheng
Shoshana Gady
Akl C. Fahed
Publication date
07-03-2024
Publisher
Springer US
Published in
Current Atherosclerosis Reports
Print ISSN: 1523-3804
Electronic ISSN: 1534-6242
DOI
https://doi.org/10.1007/s11883-024-01195-6
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