Drug development advances in human genetics-based targets

Abstract

Drug development is a long and costly process, with a high degree of uncertainty from the identification of a drug target to its market launch. Targeted drugs supported by human genetic evidence are expected to enter phase II/III clinical trials or be approved for marketing more quickly, speeding up the drug development process. Currently, genetic data and technologies such as genome-wide association studies (GWAS), whole-exome sequencing (WES), and whole-genome sequencing (WGS) have identified and validated many potential molecular targets associated with diseases. This review describes the structure, molecular biology, and drug development of human genetics-based validated beneficial loss-of-function (LOF) mutation targets (target mutations that reduce disease incidence) over the past decade. The feasibility of eight beneficial LOF mutation targets (PCSK9, ANGPTL3, ASGR1, HSD17B13, KHK, CIDEB, GPR75, and INHBE) as targets for drug discovery is mainly emphasized, and their research prospects and challenges are discussed. In conclusion, we expect that this review will inspire more researchers to use human genetics and genomics to support the discovery of novel therapeutic drugs and the direction of clinical development, which will contribute to the development of new drug discovery and drug repurposing.

Keywords

drug development / drug target / genetic variation / genome-wide association studies / whole-exome sequencing / whole-genome sequencing

References

[1] Tabana Y, Babu D, Fahlman R, Siraki AG, Barakat K. Target identification of small molecules: an overview of the current applications in drug discovery. BMC Biotechnol. 2023;23(1):44.

[2] Kabadi A, McDonnell E, Frank CL, Drowley L. Applications of functional genomics for drug discovery. SLAS Discov. 2020;25(8):823-842.

[3] Nelson MR, Tipney H, Painter JL, et al. The support of human genetic evidence for approved drug indications. Nat Genet. 2015;47(8):856-860.

[4] Visscher PM, Wray NR, Zhang Q, et al. 10 Years of GWAS discovery: biology, function, and translation. Am J Hum Genet. 2017;101(1):5-22.

[5] Sadler MC, Auwerx C, Deelen P, Kutalik Z. Multi-layered genetic approaches to identify approved drug targets. Cell Genom. 2023;3(7):100341.

[6] Ochoa D, Karim M, Ghoussaini M, Hulcoop DG, McDonagh EM, Dunham I. Human genetics evidence supports two-thirds of the 2021 FDA-approved drugs. Nat Rev Drug Discov. 2022;21(8):551.

[7] 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(7975):737-745.

[8] Davis RL. Mechanism of action and target identification: a matter of timing in drug discovery. iScience. 2020;23(9):101487.

[9] Ghoussaini M, Nelson MR, Dunham I. Future prospects for human genetics and genomics in drug discovery. Curr Opin Struct Biol. 2023;80:102568.

[10] Malone ER, Oliva M, Sabatini PJB, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome Med. 2020;12(1):8.

[11] Waarts MR, Stonestrom AJ, Park YC, Levine RL. Targeting mutations in cancer. J Clin Invest. 2022;132(8):e154943.

[12] Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28(2):165-173.

[13] Parenti I, Rabaneda LG, Schoen H, Novarino G. Neurodevelopmental disorders: from genetics to functional pathways. Trends Neurosci. 2020;43(8):608-621.

[14] Lee S, Lee JH. Brain somatic mutations as RNA therapeutic targets in neurological disorders. Ann N Y Acad Sci. 2022;1514(1):11-20.

[15] Carss KJ, Deaton AM, Del Rio-Espinola A, et al. Using human genetics to improve safety assessment of therapeutics. Nat Rev Drug Discov. 2023;22(2):145-162.

[16] Li Z, Zhang B, Liu Q, et al. Genetic association of lipids and lipid-lowering drug target genes with non-alcoholic fatty liver disease. EBioMedicine. 2023;90:104543.

[17] Li M, Li T, Xiao X, Chen J, Hu Z, Fang Y. Phenotypes, mechanisms and therapeutics: insights from bipolar disorder GWAS findings. Mol Psychiatry. 2022;27(7):2927-2939.

[18] Jiao SY, Yang YH, Chen SR. Molecular genetics of infertility: loss-of-function mutations in humans and corresponding knockout/mutated mice. J Clin Invest. 2021;27(1):154-189.

[19] Wang SS, Wang TM, Qiao XH, et al. KLF13 loss-of-function variation contributes to familial congenital heart defects. Eur Rev Med Pharmacol Sci. 2020;24(21):11273-11285.

[20] Guo YH, Wang J, Guo XJ, et al. KLF13 loss-of-function mutations underlying familial dilated cardiomyopathy. J Am Heart Assoc. 2022;11(22):e027578.

[21] Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154-156.

[22] Li AH, Morrison AC, Kovar C, et al. Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease. Nat Genet. 2015;47(6):640-642.

[23] Liu W, Sha Y, Li Y, et al. Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF). J Med Genet. 2019;56(10):678-684.

[24] Raedler LA. Praluent (Alirocumab): first PCSK9 inhibitor approved by the FDA for hypercholesterolemia. Am Health Drug Benefits. 2016;9:123-126. Spec Feature.

[25] Bujar M, Ferragu S, McAuslane N, Liberti L, Kühler TC. Transparency in European medicines agency and US food and drug administration decision making: is it possible to identify the rationale for divergences in approved indication from public assessment reports? Clin Ther. 2021;43(5):888-905.

[26] Kristjansson RP, Benonisdottir S, Davidsson OB, et al. A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis. Nat Genet. 2019;51(2):267-276.

[27] Meggendorfer M, Jobanputra V, Wrzeszczynski KO, et al. Analytical demands to use whole-genome sequencing in precision oncology. Semin Cancer Biol. 2022;84:16-22.

[28] Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol cancer. 2019;18(1):26.

[29] Na F, Pan X, Chen J, et al. KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming. Nat Cancer. 2022;3(6):753-767.

[30] Song Y, Bi Z, Liu Y, Qin F, Wei Y, Wei X. Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer: current status in clinical trials. Genes Dis. 2023;10(1):76-88.

[31] Tang F, Min L, Seebacher NA, et al. Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma. J Orthop Res. 2019;37(3):789-798.

[32] Nabirotchkin S, Peluffo AE, Rinaudo P, Yu J, Hajj R, Cohen D. Next-generation drug repurposing using human genetics and network biology. Curr Opin Pharmacol. 2020;51:78-92.

[33] Liao J, Wang Q, Wu F, Huang Z. In silico methods for identification of potential active sites of therapeutic targets. Molecules. 2022;27(20):7103.

[34] Ramharack P, Soliman MES. Bioinformatics-based tools in drug discovery: the cartography from single gene to integrative biological networks. Drug Discov Today. 2018;23(9):1658-1665.

[35] Hedl TJ, San Gil R, Cheng F, et al. Proteomics approaches for biomarker and drug target discovery in ALS and FTD. Front Neurosci. 2019;13:548.

[36] Fox CS. Using human genetics to drive drug discovery: a perspective. Am J Kidney Dis. 2019;74(1):111-119.

[37] Long E, Wan P, Chen Q, Lu Z, Choi J. From function to translation: dUsing human genetics to drive drug discovery: a perspectiveecoding genetic susceptibility to human diseases via artificial intelligence. Cell Genom. 2023;3(6):100320.

[38] Caspar SM, Schneider T, Stoll P, Meienberg J, Matyas G. Potential of whole-genome sequencing-based pharmacogenetic profiling. Pharmacogenomics. 2021;22(3):177-190.

[39] Wang RC, Wang Z. Precision medicine: disease subtyping and tailored treatment. Cancers. 2023;15(15):3837.

[40] Khunsriraksakul C, McGuire D, Sauteraud R, et al. Integrating 3D genomic and epigenomic data to enhance target gene discovery and drug repurposing in transcriptome-wide association studies. Nat Commun. 2022;13(1):3258.

[41] Baker L, Muir P, Sample SJ. Genome-wide association studies and genetic testing: understanding the science, success, and future of a rapidly developing field. J Am Vet Med Assoc. 2019;255(10):1126-1136.

[42] Ho DSW, Schierding W, Wake M, Saffery R, O'Sullivan J. Machine learning SNP based prediction for precision medicine. Front Genet. 2019;10:267.

[43] Walsh R, Jurgens SJ, Erdmann J, Bezzina CR. Genome-wide association studies of cardiovascular disease. Physiol Rev. 2023;103(3):2039-2055.

[44] Tam V, Patel N, Turcotte M, Bossé Y, Paré G, Meyre D. Benefits and limitations of genome-wide association studies. Nat Rev Genet. 2019;20(8):467-484.

[45] Wang G, Xu Y, Wang Q, et al. Rare and undiagnosed diseases: from disease-causing gene identification to mechanism elucidation. Fundam Res. 2022;2(6):918-928.

[46] López Rodríguez M, Arasu UT, Kaikkonen MU. Exploring the genetic basis of coronary artery disease using functional genomics. Atherosclerosis. 2023;374:87-98.

[47] McInnes G, Yee SW, Pershad Y, Altman RB. Genomewide association studies in pharmacogenomics. Clin Pharmacol Ther. 2021;110(3):637-648.

[48] Hingorani AD, Kuan V, Finan C, et al. Improving the odds of drug development success through human genomics: modelling study. Sci Rep. 2019;9(1):18911.

[49] Finan C, Gaulton A, Kruger FA, et al. The druggable genome and support for target identification and validation in drug development. Sci Transl Med. 2017;9(383):eaag1166.

[50] Cano-Gamez E, Trynka G. From GWAS to function: using functional genomics to identify the mechanisms underlying complex diseases. Front Genet. 2020;11:424.

[51] Spreafico R, Soriaga LB, Grosse J, Virgin HW, Telenti A. Advances in genomics for drug development. Genes. 2020;11(8):942.

[52] Lappalainen T, Scott AJ, Brandt M, Hall IM. Genomic analysis in the age of human genome sequencing. Cell. 2019;177(1):70-84.

[53] Schwarze K, Buchanan J, Taylor JC, Wordsworth S. Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Genet Med. 2018;20(10):1122-1130.

[54] Suwinski P, Ong C, Ling MHT, Poh YM, Khan AM, Ong HS. Advancing personalized medicine through the application of whole exome sequencing and big data analytics. Front Genet. 2019;10:49.

[55] Wang Q, Shashikant CS, Jensen M, Altman NS, Girirajan S. Novel metrics to measure coverage in whole exome sequencing datasets reveal local and global non-uniformity. Sci Rep. 2017;7(1):885.

[56] Glotov OS, Chernov AN, Glotov AS. Human exome sequencing and prospects for predictive medicine: analysis of international data and own experience. J Pers Med. 2023;13(8):1236.

[57] Souche E, Beltran S, Brosens E, et al. Recommendations for whole genome sequencing in diagnostics for rare diseases. Eur J Hum Genet. 2022;30(9):1017-1021.

[58] Marwaha S, Knowles JW, Ashley EA. A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Med. 2022;14(1):23.

[59] Meienberg J, Bruggmann R, Oexle K, Matyas G. Clinical sequencing: is WGS the better WES? Hum Genet. 2016;135(3):359-362.

[60] McInerney-Leo AM, Duncan EL. Massively parallel sequencing for rare genetic disorders: potential and pitfalls. Front Endocrinol (Lausanne). 2020;11:628946.

[61] Król ZJ, Dobosz P, Ślubowska A, Mroczek M. WGS data collections: how do genomic databases transform medicine? Int J Mol Sci. 2023;24(3):3031.

[62] Vockley J, Aartsma-Rus A, Cohen JL, et al. Whole-genome sequencing holds the key to the success of gene-targeted therapies. Am J Med Genet C Semin Med Genet. 2023;193(1):19-29.

[63] Gns HS, Gr S, Murahari M, Krishnamurthy M. An update on drug repurposing: re-written saga of the drug's fate. Biomed Pharmacother. 2019;110:700-716.

[64] Lang X, Liu J, Zhang G, Feng X, Dan W. Knowledge mapping of drug repositioning's theme and development. Drug Des Devel Ther. 2023;17:1157-1174.

[65] Duff CJ, Scott MJ, Kirby IT, Hutchinson SE, Martin SL, Hooper NM. Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor. Biochem J. 2009;419(3):577-584.

[66] Maligłówka M, Kosowski M, Hachuła M, et al. Insight into the evolving role of PCSK9. Metabolites. 2022;12(3):256.

[67] Hummelgaard S, Vilstrup JP, Gustafsen C, Glerup S, Weyer K. Targeting PCSK9 to tackle cardiovascular disease. Pharmacol Ther. 2023;249:108480.

[68] Bell AS, Wagner J, Rosoff DB, Lohoff FW. Proprotein convertase subtilisin/kexin type 9 (PCSK9) in the central nervous system. Neurosci Biobehav Rev. 2023;149:105155.

[69] Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet. 2006;79(3):514-523.

[70] Lebeau PF, Platko K, Byun JH, Makda Y, Austin RC. The emerging roles of intracellular PCSK9 and their implications in endoplasmic reticulum stress and metabolic diseases. Metabolites. 2022;12(3):215.

[71] Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272.

[72] Piper DE, Jackson S, Liu Q, et al. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure (London, England : 1993). 2007;15(5):545-552.

[73] Leren TP. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet. 2004;65(5):419-422.

[74] Barale C, Melchionda E, Morotti A, Russo I. PCSK9 biology and its role in atherothrombosis. Int J Mol Sci. 2021;22(11):5880.

[75] Poirier S, Hamouda HA, Villeneuve L, Demers A, Mayer G. Trafficking dynamics of PCSK9-induced LDLR degradation: focus on human PCSK9 mutations and C-terminal domain. PLoS One. 2016;11(6):e0157230.

[76] Benn M, Tybjærg-Hansen A, Nordestgaard BG. Low LDL cholesterol by PCSK9 variation reduces cardiovascular mortality. J Am Coll Cardiol. 2019;73(24):3102-3114.

[77] Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37(2):161-165.

[78] Mayne J, Ooi TC, Raymond A, et al. Differential effects of PCSK9 loss of function variants on serum lipid and PCSK9 levels in Caucasian and African Canadian populations. Lipids Health Dis. 2013;12:70.

[79] Meng FH, Liu S, Xiao J, et al. New loss-of-function mutations in PCSK9 reduce plasma LDL cholesterol. Arterioscler Thromb Vasc Biol. 2023;43(7):1219-1233.

[80] Crone B, Krause AM, Hornsby WE, Willer CJ, Surakka I. Translating genetic association of lipid levels for biological and clinical application. Cardiovasc Drugs Ther. 2021;35(3):617-626.

[81] Han SM, Hwang B, Park TG, et al. Genetic testing of Korean familial hypercholesterolemia using whole-exome sequencing. PLoS One. 2015;10(5):e0126706.

[82] Rosenson RS, Hegele RA, Fazio S, Cannon CP. The evolving future of PCSK9 inhibitors. J Am Coll Cardiol. 2018;72(3):314-329.

[83] Tavori H, Giunzioni I, Predazzi IM, et al. Human PCSK9 promotes hepatic lipogenesis and atherosclerosis development via apoE- and LDLR-mediated mechanisms. Cardiovasc Res. 2016;110(2):268-278.

[84] Sotler T, Šebeštjen M. PCSK9 as an atherothrombotic risk factor. Int J Mol Sci. 2023;24(3):1966.

[85] Basiak M, Kosowski M, Cyrnek M, et al. Pleiotropic effects of PCSK-9 inhibitors. Int J Mol Sci. 2021;22(6):3144.

[86] Scalise V, Sanguinetti C, Neri T, et al. PCSK9 induces tissue factor expression by activation of TLR4/NFkB signaling. Int J Mol Sci. 2021;22(23):12640.

[87] Xu JN, Wang TT, Shu H, Shi SY, Tao LC, Li JJ. Insight into the role of PCSK9 in glucose metabolism. Clin Chim Acta. 2023;547:117444.

[88] Mbikay M, Chrétien M. The biological relevance of PCSK9: when less is better…. Biochem Cell Biol. 2022;100(3):189-198.

[89] Lu F, Li E, Yang X. The association between circulatory, local pancreatic PCSK9 and type 2 diabetes mellitus: the effects of antidiabetic drugs on PCSK9. Heliyon. 2023;9(9):e19371.

[90] Grimaudo S, Bartesaghi S, Rametta R, et al. PCSK9 rs11591147 R46L loss-of-function variant protects against liver damage in individuals with NAFLD. Liver Int. 2021;41(2):321-332.

[91] Jakielska E, Głuszak P, Walczak M, Bryl W. Effects of PCSK9 inhibitors on metabolic-associated fatty liver disease: a short review. Prz Gastroenterol. 2023;18(2):148-153.

[92] Bhattacharya A, Chowdhury A, Chaudhury K, Shukla PC. Proprotein convertase subtilisin/kexin type 9 (PCSK9): a potential multifaceted player in cancer. Biochim Biophys Acta Rev Cancer. 2021;1876(1):188581.

[93] Picard C, Poirier A, Bélanger S, Labonté A, Auld D, Poirier J. Proprotein convertase subtilisin/kexin type 9 (PCSK9) in Alzheimer's disease: a genetic and proteomic multi-cohort study. PLoS One. 2019;14(8):e0220254.

[94] Roychowdhury T, Klarin D, Levin MG, et al. Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target. Nat Genet. 2023;55(11):1831-1842.

[95] Wang H, Guo Q, Wang M, Liu C, Tian Z. PCSK9 promotes tumor cell proliferation and migration by facilitating CCL25 secretion in esophageal squamous cell carcinoma. Oncol Lett. 2023;26(5):500.

[96] Sun C, Zhu G, Shen C, et al. Identification and validation of PCSK9 as a prognostic and immune-related influencing factor in tumorigenesis: a pan-cancer analysis. Front Oncol. 2023;13:1134063.

[97] Blom DJ, Harada-Shiba M, Rubba P, et al. Efficacy and safety of alirocumab in adults with homozygous familial hypercholesterolemia: the ODYSSEY HoFH Trial. J Am Coll Cardiol. 2020;76(2):131-142.

[98] Santos RD, Stein EA, Hovingh GK, et al. Long-term evolocumab in patients with familial hypercholesterolemia. J Am Coll Cardiol. 2020;75(6):565-574.

[99] Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382(16):1520-1530.

[100] Liu C, Chen J, Chen H, et al. PCSK9 inhibition: from current advances to evolving future. Cells. 2022;11(19):2972.

[101] Coppinger C, Movahed MR, Azemawah V, Peyton L, Gregory J, Hashemzadeh M. A comprehensive review of PCSK9 inhibitors. J Cardiovasc Pharmacol Ther. 2022;27:10742484221100107.

[102] Giunzioni I, Tavori H. New developments in atherosclerosis: clinical potential of PCSK9 inhibition. Vasc Health Risk Manag. 2015;11:493-501.

[103] Raschi E, Casula M, Cicero AFG, Corsini A, Borghi C, Catapano A. Beyond statins: new pharmacological targets to decrease LDL-cholesterol and cardiovascular events. Pharmacol Ther. 2023:108507.

[104] Kasichayanula S, Grover A, Emery MG, et al. Clinical pharmacokinetics and pharmacodynamics of evolocumab, a PCSK9 inhibitor. Clin Pharmacokinet. 2018;57(7):769-779.

[105] Evolocumab as an adjunct to statins for CVD. Drug Ther Bull. 2017;55(7):76-77.

[106] Zhang J, Tecson KM, Rocha NA, McCullough PA. Usefulness of alirocumab and evolocumab for the treatment of patients with diabetic dyslipidemia. Proc (Bayl Univ Med Cent). 2018;31(2):180-184.

[107] Butt WZ, Yee JK. The role of non-statin lipid-lowering medications in youth with hypercholesterolemia. Curr Atheroscler Rep. 2022;24(5):379-389.

[108] Lamb YN. Inclisiran: first approval. Drugs. 2021;81(3):389-395.

[109] Soffer D, Stoekenbroek R, Plakogiannis R. Small interfering ribonucleic acid for cholesterol lowering—Inclisiran: inclisiran for cholesterol lowering. J Clin Lipidol. 2022;16(5):574-582.

[110] Al Shaer D, Al Musaimi O, Albericio F, de la Torre BG. 2021 FDA tides (peptides and oligonucleotides) harvest. Pharmaceuticals (Basel). 2022;15(2):222.

[111] Qi L, Liu D, Qu Y, et al. Tafolecimab in Chinese patients with hypercholesterolemia (CREDIT-4): a randomized, double-blind, placebo-controlled Phase 3 trial. JACC: Asia. 2023;3(4):636-645.

[112] Li JJ. Tafolecimab, A novel member of PCSK9 monoclonal antibodies, is worth expecting in a Chinese population. JACC Asia. 2023;3(4):646-648.

[113] Shanghai Junshi Bioscience Co. L. The safety and efficacy of multiple-dose of JS002 in subject with hyperlipidemia. Clinicaltrials.gov. Accessed August 21, 2023.

[114] Akeso. A study to evaluate the Long-term efficacy and safety of AK102 in patients with hyperlipidemia. Clinicaltrials.gov. Accessed August 10, 2023.

[115] Inc. AB. NMPA accepted Akeso's ebronucimab (PCSK9) marketing application in two indications. Akeso Biopharma Inc. Accessed November 15, 2023.

[116] Xu M, Zhu X, Wu J, et al. PCSK9 inhibitor recaticimab for hypercholesterolemia on stable statin dose: a randomized, double-blind, placebo-controlled phase 1b/2 study. BMC Med. 2022;20(1):13.

[117] Jiangsu HengRui Medicine Co L. Study of SHR-1209 in the treatment of hypercholesterolemia and hyperlipidemia III stage. Clinicaltrials.gov. Accessed July 18, 2023.

[118] Ltd JHMC. R&D pipelines. Jiangsu Hengrui Medicine Co Ltd. Accessed November 15, 2023.

[119] LLC LIBT, Medpace I. Long-term efficacy and safety of OLE LIB003 in HoFH, HeFH, and high-risk CVD patients requiring further LDL-C reduction. Clinicaltrials.gov. Accessed August 13, 2023.

[120] Raheem Lateef Al-Awsi G, Hadi Lafta M, Hashim Kzar H, et al. PCSK9 pathway-noncoding RNAs crosstalk: emerging opportunities for novel therapeutic approaches in inflammatory atherosclerosis. Int Immunopharmacol. 2022;113:109318.

[121] Ballantyne CM, Banka P, Mendez G, et al. Phase 2b randomized trial of the oral PCSK9 inhibitor MK-0616. J Am Coll Cardiol. 2023;81(16):1553-1564.

[122] Gupta K, Balachandran I, Foy J, et al. Highlights of cardiovascular disease prevention studies presented at the 2023 American college of cardiology conference. Curr Atheroscler Rep. 2023;25(6):309-321.

[123] Merck S, Dohme LLC. A study of MK-0616 (oral PCSK9 inhibitor) in adults with heterozygous familial hypercholesterolemia (MK-0616-017) CORALreef HeFH. Clinicaltrialsgov. Accessed November 15, 2023.

[124] Merck S, Dohme LLC. MK-0616 (oral PCSK9 inhibitor) cardiovascular outcomes study (MK-0616-015) CORALreef outcomes. Clinicaltrialsgov. Accessed November 15, 2023.

[125] AstraZeneca. A study of AZD8233 in participants with dyslipidemia. Clinicaltrials.gov. Accessed August 2, 2023.

[126] Xu S, Luo S, Zhu Z, Xu J. Small molecules as inhibitors of PCSK9: current status and future challenges. Eur J Med Chem. 2019;162:212-233.

[127] Civi Biopharma I. Phase 2a study to assess CIVI 007 in patients on a background of statin therapy. Clinicaltrials.gov. Accessed July 25, 2023.

[128] Gouni-Berthold I, Schwarz J, Berthold HK. PCSK9 monoclonal antibodies: new developments and their relevance in a nucleic acid-based therapy era. Curr Atheroscler Rep. 2022;24(10):779-790.

[129] Hermel M, Lieberman M, Slipczuk L, Rana JS, Virani SS. Monoclonal antibodies, gene silencing and gene editing (CRISPR) therapies for the treatment of hyperlipidemia-the future is here. Pharmaceutics. 2023;15(2):459.

[130] Warden BA, Fazio S, Shapiro MD. The PCSK9 revolution: current status, controversies, and future directions. Trends Cardiovasc Med. 2020;30(3):179-185.

[131] Janik E, Niemcewicz M, Ceremuga M, Krzowski L, Saluk-Bijak J, Bijak M. Various aspects of a gene editing system-CRISPR-Cas9. Int J Mol Sci. 2020;21(24):9604.

[132] Kersten S. ANGPTL3 as therapeutic target. Curr Opin Lipidol. 2021;32(6):335-341.

[133] Geladari E, Tsamadia P, Vallianou NG. ANGPTL3 Inhibitors—their role in cardiovascular disease through regulation of lipid metabolism. Circ J. 2019;83(2):267-273.

[134] Srivastava RAK. A review of progress on targeting LDL receptor-dependent and -independent pathways for the treatment of hypercholesterolemia, a major risk factor of ASCVD. Cells. 2023;12(12):1648.

[135] Ward NC, Chan DC, Watts GF. A tale of two new targets for hypertriglyceridaemia: which choice of therapy? BioDrugs. 2022;36(2):121-135.

[136] Koishi R, Ando Y, Ono M, et al. Angptl3 regulates lipid metabolism in mice. Nat Genet. 2002;30(2):151-157.

[137] Wang X, Musunuru K. Angiopoietin-Like 3: from discovery to therapeutic gene editing. JACC Basic Transl Sci. 2019;4(6):755-762.

[138] Cohen JC. Using human genetics to discover new therapeutic targets for plasma lipids. J Intern Med. 2016;280(5):487-495.

[139] Romeo S, Yin W, Kozlitina J, et al. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J Clin Invest. 2009;119(1):70-79.

[140] Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med. 2017;377(3):211-221.

[141] Kosmas CE, Bousvarou MD, Sourlas A, et al. Angiopoietin-Like Protein 3 (ANGPTL3) inhibitors in the management of refractory hypercholesterolemia. Clin Pharmacol. 2022;14:49-59.

[142] Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol. 2017;69(16):2054-2063.

[143] Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010;363(23):2220-2227.

[144] Robciuc MR, Maranghi M, Lahikainen A, et al. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol. 2013;33(7):1706-1713.

[145] Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med. 2017;377(3):222-232.

[146] Ginsberg HN, Goldberg IJ. Broadening the scope of dyslipidemia therapy by targeting APOC3 (Apolipoprotein C3) and ANGPTL3 (Angiopoietin-like protein 3). Arterioscler Thromb Vasc Biol. 2023;43(3):388-398.

[147] Mohamed F, Mansfield BS, Raal FJ. ANGPTL3 as a drug target in hyperlipidemia and atherosclerosis. Curr Atheroscler Rep. 2022;24(12):959-967.

[148] Burks KH, Basu D, Goldberg IJ, Stitziel NO. Angiopoietin-like 3: an important protein in regulating lipoprotein levels. Best Pract Res Clin Endocrinol Metab. 2023;37(3):101688.

[149] Christopoulou E, Elisaf M, Filippatos T. Effects of Angiopoietin-like 3 on triglyceride regulation, glucose homeostasis, and diabetes. Dis Markers. 2019;2019:6578327.

[150] Kersten S. Physiological regulation of lipoprotein lipase. Biochim Biophys Acta. 2014;1841(7):919-933.

[151] McCoy MG, Sun GS, Marchadier D, Maugeais C, Glick JM, Rader DJ. Characterization of the lipolytic activity of endothelial lipase. J Lipid Res. 2002;43(6):921-929.

[152] Wang Y, Gusarova V, Banfi S, Gromada J, Cohen JC, Hobbs HH. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res. 2015;56(7):1296-1307.

[153] Luo F, Das A, Khetarpal SA, et al. ANGPTL3 inhibition, dyslipidemia, and cardiovascular diseases. Trends Cardiovasc Med. 2023;S1050-1738(23):00018-X.

[154] Wu L, Soundarapandian MM, Castoreno AB, Millar JS, Rader DJ. LDL-cholesterol reduction by ANGPTL3 inhibition in mice is dependent on endothelial lipase. Circ Res. 2020;127(8):1112-1114.

[155] Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in patients with refractory hypercholesterolemia. N Engl J Med. 2020;383(24):2307-2319.

[156] Shimamura M, Matsuda M, Ando Y, et al. Leptin and insulin down-regulate angiopoietin-like protein 3, a plasma triglyceride-increasing factor. Biochem Biophys Res Commun. 2004;322(3):1080-1085.

[157] Ruhanen H, Haridas PAN, Jauhiainen M, Olkkonen VM. Angiopoietin-like protein 3, an emerging cardiometabolic therapy target with systemic and cell-autonomous functions. Biochim Biophys Acta Mol Cell Biol Lipids. 2020;1865(12):158791.

[158] El-Shal AS, Zidan HE, Rashad NM, Wadea FM. Angiopoietin-like protein 3 and 4 expression 4 and their serum levels in hepatocellular carcinoma. Cytokine. 2017;96:75-86.

[159] Wu Y, Zheng Y, Jin Z. ANGPTL3 affects the metastatic potential and the susceptibility of ovarian cancer cells to natural killer cell-mediated cytotoxicity. Heliyon. 2023;9(8):e18799.

[160] Kim JY, Moon S, Kim D. Oral squamous cell carcinoma-derived ANGPTL3 induces cancer associated fibroblastic phenotypes in surrounding fibroblasts. Asian Pac J Cancer Prev. 2022;23(12):4315-4322.

[161] Pirillo A, Catapano AL, Norata GD. Monoclonal antibodies in the management of familial hypercholesterolemia: focus on PCSK9 and ANGPTL3 inhibitors. Curr Atheroscler Rep. 2021;23(12):79.

[162] Rhee JW, Wu JC. Dyslipidaemia: in vivo genome editing of ANGPTL3: a therapy for atherosclerosis? Nat Rev Cardiol. 2018;15(5):259-260.

[163] Oostveen RF, Hovingh GK, Stroes ESG. Angiopoietin-like 3 inhibition and the liver: less is more? Curr Opin Lipidol. 2023;34(6):267-271.

[164] Sosnowska B, Adach W, Surma S, Rosenson RS, Banach M. Evinacumab, an ANGPTL3 inhibitor, in the treatment of dyslipidemia. J Clin Med. 2022;12(1):168.

[165] Markham A. Evinacumab: first a sudy of ARO-ANG3 in participants with homozygous familial hypercholesterolemia (HOFH) proval. Drugs. 2021;81(9):1101-1105.

[166] Watts GF, Raal FJ, Chan DC. Transcriptomic therapy for dyslipidemias utilizing nucleic acids targeted at ANGPTL3. Future Cardiol. 2022;18(2):143-153.

[167] Gaudet D, Karwatowska-Prokopczuk E, Baum SJ, et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur Heart J. 2020;41(40):3936-3945.

[168] Pharmaceuticals A. Study of ARO-ANG3 in participants with homozygous familial hypercholesterolemia (HOFH). Clinicaltrials.gov. Accessed June 20, 2023.

[169] Pharmaceuticals A. Study of ARO-ANG3 in adults with mixed dyslipidemia. Clinicaltrials.gov. Accessed August 06, 2023.

[170] Pfizer. A dose-ranging study with Vupanorsen (TRANSLATE-TIMI 70). Clinicaltrials.gov. Accessed July 21, 2023.

[171] Pharmaceuticals N. A safety and efficacy study of anti-inflammatory (Canakinumab) and cartilage stimulating (LNA043) drugs injected into the knee joint of participants with knee osteoarthritis (OA). Clinicaltrials.gov. Accessed June 21, 2023.

[172] Pharmaceuticals N. Study of efficacy, safety, and tolerability of LNA043 in patients with knee osteoarthritis. Clinicaltrials.gov. Accessed August 21, 2023.

[173] Company ELa. A study of LY3561774 in participants with mixed dyslipidemia. Clinicaltrials.gov. Accessed July 18, 2023.

[174] Company ELa. A study of LY3561774 in participants with dyslipidemia. Clinicaltrials.gov. Accessed August 6, 2023.

[175] Company ELa. A study of LY3475766 in healthy participants. Clinicaltrials.gov. Accessed July 26, 2023.

[176] Verve Therapeutics I. A study of VERVE-101 in patients with familial hypercholesterolemia and cardiovascular disease. Clinicaltrials.gov. Updated May 31, 2022. Accessed August 1, 2023.

[177] Center For Drug Evaluation N. Browse the catalog of accepted varieties. Center For Drug Evaluation, NMPA. Accessed August 21, 2023.

[178] Inc VT. Our ANGPTL3 program. Verve Therapeutics Inc. Accessed July 21, 2023.

[179] Therapeutics C. Pipeline. CRISPR Therapeutics. Accessed August 20, 2023.

[180] Ltd, SRLSC. Pipeline. Suzhou Ribo Life Science Co Ltd, Accessed August 18, 2023.

[181] Carugo S, Sirtori CR, Gelpi G, Corsini A, Tokgozoglu L, Ruscica M. Updates in small interfering RNA for the treatment of dyslipidemias. Curr Atheroscler Rep. 2023;25(11):805-817.

[182] Macchi C, Sirtori CR, Corsini A, Santos RD, Watts GF, Ruscica M. A new dawn for managing dyslipidemias: the era of rna-based therapies. Pharmacol Res. 2019;150:104413.

[183] Fukami H, Morinaga J, Nakagami H, et al. Efficacy and safety in mice of repeated, lifelong administration of an ANGPTL3 vaccine. npj Vaccines. 2023;8(1):168.

[184] Wang J-Q, Li L-L, Hu A, et al. Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion. Nature. 2022;608(7922):413-420.

[185] Zhao W, Xu S, Weng J. ASGR1: an emerging therapeutic target in hypercholesterolemia. Signal Transduct Target Ther. 2023;8(1):43.

[186] Susan-Resiga D, Girard E, Essalmani R, et al. Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin. J Biol Chem. 2021;297(4):101177.

[187] Kinberger GA, Prakash TP, Yu J, et al. Conjugation of mono and di-GalNAc sugars enhances the potency of antisense oligonucleotides via ASGR mediated delivery to hepatocytes. Bioorg Med Chem Lett. 2016;26(15):3690-3693.

[188] Tanowitz M, Hettrick L, Revenko A, Kinberger GA, Prakash TP, Seth PP. Asialoglycoprotein receptor 1 mediates productive uptake of N-acetylgalactosamine-conjugated and unconjugated phosphorothioate antisense oligonucleotides into liver hepatocytes. Nucleic Acids Res. 2017;45(21):12388-12400.

[189] Nioi P, Sigurdsson A, Thorleifsson G, et al. Variant ASGR1 associated with a reduced risk of coronary artery disease. N Engl J Med. 2016;374(22):2131-2141.

[190] Ali L, Cupido AJ, Rijkers M, et al. Common gene variants in ASGR1 gene locus associate with reduced cardiovascular risk in absence of pleiotropic effects. Atherosclerosis. 2020;306:15-21.

[191] Xie B, Shi X, Li Y, et al. Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans. PLoS Genet. 2021;17(11):e1009891.

[192] Xu Y, Tao J, Yu X, et al. Hypomorphic ASGR1 modulates lipid homeostasis via INSIG1-mediated SREBP signaling suppression. JCI Insight. 2021;6(19):e147038.

[193] Grozovsky R, Begonja AJ, Liu K, et al. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med. 2015;21(1):47-54.

[194] Gu D, Jin H, Jin G, et al. The asialoglycoprotein receptor suppresses the metastasis of hepatocellular carcinoma via LASS2-mediated inhibition of V-ATPase activity. Cancer letters. 2016;379(1):107-116.

[195] Shi R, Wang J, Zhang Z, Leng Y, Chen AF. ASGR1 promotes liver injury in sepsis by modulating monocyte-to-macrophage differentiation via NF-κB/ATF5 pathway. Life Sci. 2023;315:121339.

[196] Scott LJ. Givosiran: first approval. Drugs. 2020;80(3):335-339.

[197] Scott LJ, Keam SJ. Lumasiran: first approval. Drugs. 2021;81(2):277-282.

[198] Keam SJ. Vutrisiran: first approval. Drugs. 2022;82(13):1419-1425.

[199] FDA. Drugs@FDA: FDA-approved drugs. FDA. Accessed November 28, 2023.

[200] Gao S, Wang L, Bai F, Xu S. In silico discovery of food-derived phytochemicals against asialoglycoprotein receptor 1 for treatment of hypercholesterolemia: pharmacophore modeling, molecular docking and molecular dynamics simulation approach. J Mol Graphics Modell. 2023;125:108614.

[201] Janiszewski M, Sohn W, Su C, Hsu YH, Finger E, Kaufman A. A rendomized, placebo-controlled, double-blind, ascending single-dose, phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and pharacodynamics of AMG 529, a novel anti-ASGR1 monoclonal antibody, in healthy subjects. J Am Coll Cardiol. 2019;73(9):1755. Supplement 1.

[202] Stickel F, Lutz P, Buch S, et al. Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers. Hepatology (Baltimore, Md). 2020;72(1):88-102.

[203] Ma Y, Karki S, Brown PM, et al. Characterization of essential domains in HSD17B13 for cellular localization and enzymatic activity. J Lipid Res. 2020;61(11):1400-1409.

[204] Dong XC. A closer look at the mysterious HSD17B131. J Lipid Res. 2020;61(11):1361-1362.

[205] Liu S, Sommese RF, Nedoma NL, et al. Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13. Nat Commun. 2023;14(1):5158.

[206] Ma Y, Belyaeva OV, Brown PM, et al. 17-Beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease. Hepatology. 2019;69(4):1504-1519.

[207] Ma Y, Brown PM, Lin DD, et al. 17-Beta hydroxysteroid dehydrogenase 13 deficiency does not protect mice from obesogenic diet injury. Hepatology. 2021;73(5):1701-1716.

[208] Wang M-X, Peng Z-G. 17β-hydroxysteroid dehydrogenases in the progression of nonalcoholic fatty liver disease. Pharmacol Ther. 2023;246:108428.

[209] Dong XC. A closer look at the mysterious HSD17B13. J Lipid Res. 2020;61(11):1361-1362.

[210] Wang M, Li J, Li H, et al. Down-regulating the high level of 17-beta-hydroxysteroid dehydrogenase 13 plays a therapeutic role for non-alcoholic fatty liver disease. Int J Mol Sci. 2022;23(10):5544.

[211] Su W, Wang Y, Jia X, et al. Comparative proteomic study reveals 17β-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease. Proc Natl Acad Sci USA. 2014;111(31):11437-11442.

[212] Abul-Husn NS, Cheng X, Li AH, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018;378(12):1096-1106.

[213] Verweij N, Haas ME, Nielsen JB, et al. Germline mutations in CIDEB and protection against liver disease. N Engl J Med. 2022;387(4):332-344.

[214] Yang J, Trépo E, Nahon P, et al. A 17-beta-hydroxysteroid dehydrogenase 13 variant protects from hepatocellular carcinoma development in alcoholic liver disease. Hepatology. 2019;70(1):231-240.

[215] Chen H, Zhang Y, Guo T, et al. Genetic variant rs72613567 of HSD17B13 gene reduces alcohol-related liver disease risk in Chinese Han population. Liver Int. 2020;40(9):2194-2202.

[216] Kallwitz E, Tayo BO, Kuniholm MH, et al. Association of HSD17B13 rs72613567:tA with non-alcoholic fatty liver disease in Hispanics/Latinos. Liver Int. 2020;40(4):889-893.

[217] Vilar-Gomez E, Pirola CJ, Sookoian S, Wilson LA, Liang T, Chalasani N. The protection conferred by HSD17B13 rs72613567 polymorphism on risk of steatohepatitis and fibrosis may be limited to selected subgroups of patients with NAFLD. Clin Transl Gastroenterol. 2021;12(9):e00400.

[218] Hudert CA, Adams LA, Alisi A, et al. Variants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17-beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms. Hepatol Commun. 2022;6(8):1934-1948.

[219] Luukkonen PK, Tukiainen T, Juuti A, et al. Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI insight. 2020;5(5):e132158.

[220] Rotroff DM, Pijut SS, Marvel SW, et al. Genetic variants in HSD17B3, SMAD3, and IPO11 impact circulating lipids in response to fenofibrate in individuals with type 2 diabetes. Clin Pharmacol Ther. 2018;103(4):712-721.

[221] Adam M, Heikelä H, Sobolewski C, et al. Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice. FASEB J. 2018;32(6):3434-3447.

[222] Saeed A, Dullaart RPF, Schreuder T, Blokzijl H, Faber KN. Disturbed vitamin a metabolism in non-alcoholic fatty liver disease (NAFLD). Nutrients. 2017;10(1):29.

[223] Luukkonen PK, Sakuma I, Gaspar RC, et al. Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis. Proc Natl Acad Sci U S A. 2023;120(4):e2217543120.

[224] Anstee QM, Darlay R, Cockell S, et al. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort^☆. J Hepatol. 2020;73(3):505-515.

[225] Mak L-Y, Gane E, Schwabe C, et al. A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis. J Hepatol. 2022;78(4):684-692.

[226] Zhang HB, Su W, Xu H, Zhang XY, Guan YF. HSD17B13: a potential therapeutic target for NAFLD. Front Mol Biosci. 2021;8:824776.

[227] Mak L-Y, Gane E, Schwabe C, et al. A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis. J Hepatol. 2023;78(4):684-692.

[228] Pharmaceuticals. A. Study of ARO-HSD in healthy volunteers and patients with non-alcoholic steatohepatitis (NASH) or suspected NASH. Clinicaltrials.gov. Accessed July 13, 2023.

[229] Therapeutics V. Clinical pipeline. Visirna Therapeutics. Accessed August 18, 2023.

[230] Pharmaceuticals R. A study to evaluate the efficacy and safety of ALN-HSD in adult participants with non-alcoholic steatohepatitis (NASH) with fibrosis with genetic risk factors. Clinicaltrials.gov. Accessed July 13, 2023.

[231] IAP Ltd . A study of INI-822 in healthy volunteers and participants with non-alcoholic steatohepatitis (NASH) or presumed NASH. Clinicaltrials.gov. Accessed August 6, 2023.

[232] AstraZeneca. Knockdown of HSD17B13 mRNA, pharmacokinetics, safety, and tolerability, of AZD7503 in non-alcoholic fatty liver disease. Clinicaltrials.gov. Accessed November 15, 2023.

[233] AstraZeneca. A study to assess the safety, tolerability and pharmacokinetics of AZD7503 in healthy participants. Clinicaltrials.gov. Accessed November 23, 2023.

[234] Science RL. Product development pipelines. Ribo Life Science. Accessed November 23, 2023.

[235] Thamm S, Willwacher MK, Aspnes GE, et al. Discovery of a novel potent and selective HSD17B13 inhibitor, BI-3231, a well-characterized chemical probe available for open science. J Med Chem. 2023;66(4):2832-2850.

[236] Ishimoto T, Lanaspa MA, Le MT, et al. Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. Proc Natl Acad Sci USA. 2012;109(11):4320-4325.

[237] Herman MA, Samuel VT. The sweet path to metabolic demise: fructose and lipid synthesis. Trends Endocrinol Metab. 2016;27(10):719-730.

[238] Jang C, Hui S, Lu W, et al. The small intestine converts dietary fructose into glucose and organic acids. Cell Metab. 2018;27(2):351-361. e3.

[239] Bonthron DT, Brady N, lA Donaldson, Steinmann B. Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet. 1994;3(9):1627-1631.

[240] Jiang H, Lin Q, Ma L, et al. Fructose and fructose kinase in cancer and other pathologies. J Genet Genomics. 2021;48(7):531-539.

[241] Bonthron DT, Brady N, Donaldson IA, Steinmann B. Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet. 1994;3(9):1627-1631.

[242] Ferraris RP, Choe JY, Patel CR. Intestinal absorption of fructose. Annu Rev Nutr. 2018;38:41-67.

[243] Lanaspa MA, Andres-Hernando A, Orlicky DJ, et al. Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. J Clin Invest. 2018;128(6):2226-2238.

[244] Andres-Hernando A, Orlicky DJ, Kuwabara M, et al. Deletion of fructokinase in the liver or in the intestine reveals differential effects on sugar-induced metabolic dysfunction. Cell Metab. 2020;32(1):117-127. e3.

[245] Hannou SA, Haslam DE, McKeown NM, Herman MA. Fructose metabolism and metabolic disease. J Clin Invest. 2018;128(2):545-555.

[246] Zhang C, Li L, Zhang Y, Zeng C. Recent advances in fructose intake and risk of hyperuricemia. Biomed Pharmacother. 2020;131:110795.

[247] Ter Horst KW, Serlie MJ. Fructose consumption, lipogenesis, and non-alcoholic fatty liver disease. Nutrients. 2017;9(9):981.

[248] Inci MK, Park S-H, Helsley RN, Attia SL, Softic S. Fructose impairs fat oxidation: implications for the mechanism of western diet-induced NAFLD. J Nutr Biochem. 2023;114:109224.

[249] Kim MS, Krawczyk SA, Doridot L, et al. ChREBP regulates fructose-induced glucose production independently of insulin signaling. J Clin Invest. 2016;126(11):4372-4386.

[250] Gutierrez JA, Liu W, Perez S, et al. Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction. Mol Metab. 2021;48:101196.

[251] Shepherd EL, Saborano R, Northall E, et al. Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis. JHEP Rep. 2021;3(2):100217.

[252] Bennett BJ, Davis RC, Civelek M, et al. Genetic architecture of atherosclerosis in mice: a systems genetics analysis of common inbred strains. PLoS Genet. 2015;11(12):e1005711.

[253] Febbraio MA, Karin M. “Sweet death”: fructose as a metabolic toxin that targets the gut-liver axis. Cell Metab. 2021;33(12):2316-2328.

[254] Park S-H, Helsley RN, Fadhul T, et al. Fructose induced KHK-C can increase ER stress independent of its effect on lipogenesis to drive liver disease in diet-induced and genetic models of NAFLD. Metabolism. 2023;145:155591.

[255] Li X, Qian X, Peng LX, et al. A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation. Nat Cell Biol. 2016;18(5):561-571.

[256] Guccini I, Tang G, To TT, et al. Genetic ablation of ketohexokinase C isoform impairs pancreatic cancer development. iScience. 2023;26(8):107368.

[257] Yang J, Yang S, Wang Q, et al. KHK-A promotes the proliferation of oesophageal squamous cell carcinoma through the up-regulation of PRPS1. Arab J Gastroenterol. 2021;22(1):40-46.

[258] Gao W, Li N, Li Z, Xu J, Su C. Ketohexokinase is involved in fructose utilization and promotes tumor progression in glioma. Biochem Biophys Res Commun. 2018;503(3):1298-1306.

[259] Softic S, Gupta MK, Wang GX, et al. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest. 2017;127(11):4059-4074.

[260] Weng Y, Fonseca KR, Bi YA, et al. Transporter-enzyme interplay in the pharmacokinetics of PF-06835919, a first-in-class ketohexokinase inhibitor for metabolic disorders and non-alcoholic fatty liver disease. Drug Metab Dispos. 2022.

[261] Kazierad DJ, Chidsey K, Somayaji VR, Bergman AJ, Birnbaum MJ, Calle RA. Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and inflammatory markers: a randomized phase 2 trial. Med. 2021;2(7):800-813. e3.

[262] Pfizer. A double-blind study to assess 2 doses of an investigational product for 16 weeks in participants with non-alcoholic fatty liver disease and type 2 diabetes mellitus. Clinicaltrials.gov. Accessed October 22, 2023.

[263] Pharmaceuticals A. A phase 1/2 study to evaluate ALN-KHK in overweight to obese healthy volunteers and obese patients with T2DM. Clinicaltrials.gov. Accessed October 22, 2023.

[264] Company EL. A study of LY3478045 in healthy participants. Clinicaltrials.gov. Accessed October 23, 2023.

[265] Company EL. A study of LY3522348 in healthy participants. Clinicaltrials.gov. Accessed October 22, 2023.

[266] Ping Z, Guo Z, Lu M, Chen Y, Liu L. Association of CIDEB gene promoter methylation with overweight or obesity in adults. Aging. 2022;14(8):3607-3616.

[267] Chen FJ, Yin Y, Chua BT, Li P. CIDE family proteins control lipid homeostasis and the development of metabolic diseases. Traffic. 2020;21(1):94-105.

[268] Ye J, Li JZ, Liu Y, et al. Cideb, an ER- and lipid droplet-associated protein, mediates VLDL lipidation and maturation by interacting with apolipoprotein B. Cell Metab. 2009;9(2):177-190.

[269] DeBosch BJ. A deCIDEdly new germline mutation that protects against liver disease. Gastroenterology. 2023;164(2):304-305.

[270] Su L, Zhou L, Chen FJ, et al. Cideb controls sterol-regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites. EMBO J. 2019;38(8):e100156.

[271] Sun C, Zhao Y, Gao X, et al. Cideb deficiency aggravates dextran sulfate sodium-induced uicerative colitis in mice by exacerbating the oxidative burden in colonic mucosa. Inflamm Bowel Dis. 2017;23(8):1338-1347.

[272] Zhu H, Wang Z, Li L, inventors; The Board of Regents of the University of Texas System, assignee. Compositions and methods for treating liver diseases with siRNAs targeting CIDEB. patent WO2023197001. patent application WO2023-US65557. 2023-10-12.

[273] Zuber J, McIninch JD, Schlegel MK, Castoreno A, Bondurant L, Oza D, inventors; Alnylam Pharmaceuticals, Inc., assignee. Cell death-inducing DFFA-like effector B siRNA compositions and methods for therapy. patent WO2023034837. patent application WO2022-US75715. 2023-03-09.

[274] Garcia V, Gilani A, Shkolnik B, et al. 20-HETE signals through G-protein-coupled receptor GPR75 (G(q)) to affect vascular function and trigger hypertension. Circ Res. 2017;120(11):1776-1788.

[275] Murtaza B, Asghar F, Patoli D. GPR75: an exciting new target in metabolic syndrome and related disorders. Biochimie. 2022;195:19-26.

[276] Pascale JV, Park EJ, Adebesin AM, Falck JR, Schwartzman ML, Garcia V. Uncovering the signalling, structure and function of the 20-HETE-GPR75 pairing: identifying the chemokine CCL5 as a negative regulator of GPR75. Br J Pharmacol. 2021;178(18):3813-3828.

[277] Akbari P, Gilani A, Sosina O, et al. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science. 2021;373(6550):eabf8683.

[278] Hossain S, Gilani A, Pascale J, et al. Gpr75-deficient mice are protected from high-fat diet-induced obesity. Obesity (Silver Spring). 2023;31(4):1024-1037.

[279] Powell DR, Doree DD, DaCosta CM, et al. Mice lacking Gpr75 are hypophagic and thin. Diabetes Metab Syndr Obes. 2022;15:45-58.

[280] Choi J, Kim S, Kim J, et al. A whole-genome reference panel of 14,393 individuals for East Asian populations accelerates discovery of rare functional variants. Sci Adv. 2023;9(32):eadg6319.

[281] Cárdenas S, Colombero C, Panelo L, et al. GPR75 receptor mediates 20-HETE-signaling and metastatic features of androgen-insensitive prostate cancer cells. Biochim Biophys Acta Mol Cell Biol Lipids. 2020;1865(2):158573.

[282] Fan F, Roman RJ. GPR75 identified as the first 20-HETE receptor: a chemokine receptor adopted by a new family. Circ Res. 2017;120(11):1696-1698.

[283] D'Addario C, Kitagawa A, Matsumura S, et al. Deletion of G-protein-coupled receptor 75 prevents hypoxia-induced pulmonary vasoconstriction and hypertension. FASEB J. 2022;36(S1).

[284] D'Addario C, Kitagawa A, Zhang F, et al. G protein coupled receptor 75 and its role in pulmonary hypertension. FASEB J. 2020;34(S1):1-1.

[285] Dashti MR, Gorbanzadeh F, Jafari-Gharabaghlou D, Farhoudi Sefidan Jadid M, Zarghami N. G protein-coupled receptor 75 (GPR75) as a novel molecule for targeted therapy of cancer and metabolic syndrome. Asian Pac J Cancer Prev. 2023;24(5):1817-1825.

[286] Murtaza B, Asghar F, Patoli D. GPR75: an exciting new target in metabolic syndrome and related disorders. Biochimie. 2022;195:19-26.

[287] Laschet C, Dupuis N, Hanson J. The G protein-coupled receptors deorphanization landscape. Biochem Pharmacol. 2018;153:62-74.

[288] Dedoni S, Campbell LA, Harvey BK, Avdoshina V, Mocchetti I. The orphan G-protein-coupled receptor 75 signaling is activated by the chemokine CCL5. J Neurochem. 2018;146(5):526-539.

[289] Med B. New drug pipelines. BeBetter Med. Accessed November 12, 2023.

[290] McIninch JD, Bostwick BL, Castoreno A, inventors; Alnylam Pharmaceuticals, Inc. Regeneron Pharmaceuticals, Inc., assignee. G protein-coupled receptor 75 (GPR75) interfering RNA compositions and methods of use thereof. patent WO2022076291. patent application WO2021-US53332. 2022-04-14.

[291] Lotta LA, Ferreira MAR, Baras A, Akbari P, Sosina O, inventors; Regeneron Pharmaceuticals, Inc., assignee. Preparation of G-protein coupled receptor 75 inhibitors for treatment of obesity. patent WO2021262601. patent application WO2021-US38260. 2021-12-30.

[292] Deaton AM, Dubey A, Ward LD, et al. Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity. Nat Commun. 2022;13(1):4319.

[293] Griffin JD, Buxton JM, Culver JA, et al. Hepatic Activin E mediates liver-adipose inter-organ communication, suppressing adipose lipolysis in response to elevated serum fatty acids. Mol Metab. 2023;78:101830.

[294] Adam RC, Pryce DS, Lee JS, et al. Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice. Proc Natl Acad Sci USA. 2023;120(32):e2309967120.

[295] Sugiyama M, Kikuchi A, Misu H, et al. Inhibin βE (INHBE) is a possible insulin resistance-associated hepatokine identified by comprehensive gene expression analysis in human liver biopsy samples. PLoS One. 2018;13(3):e0194798.

[296] Akbari P, Sosina OA, Bovijn J, et al. Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes. Nat Commun. 2022;13(1):4844.

[297] Cao J, Zhong Q, Huang Y, Zhu M, Wang Z, Xiong Z. Identification and validation of INHBE and P4HA1 as hub genes in non-alcoholic fatty liver disease. Biochem Biophys Res Commun. 2023;686:149180.

[298] Wen W, Wu P, Zhang Y, Chen Z, Sun J, Chen H. Comprehensive analysis of NAFLD and the therapeutic target identified. Front Cell Dev Biol. 2021;9:704704.

[299] Xu ZB, Gan MF, Yu HY, et al. The significance of INHBE expression in the cancer cells of clear-cell renal cell carcinoma. Urol Int. 2022;106(4):376-386.

[300] Inc AP. Alnylam uncovers genetic mutations in INHBE that protect against abdominal obesity. Alnylam Pharmaceuticals Inc. Accessed November 27, 2023.

[301] Deaton AM, Zuber J, inventors; Alnylam Pharmaceuticals, Inc., assignee. Metabolic disorder-associated target gene iRNA compositions and methods of use thereof. patent WO2023003922. patent application WO2022-US37658. 2023-01-26.

[302] Deaton AM, inventor; Alnylam Pharmaceuticals, Inc., assignee. Preparation of inhibin subunit βE expression modulators for treatment of diseases. patent WO2023044094. patent application WO2022-US43948. 2023-03-23.

[303] Lotta LA, Akbari P, Sosina O, Ferreira MAR, Baras A, inventors; Regeneron Pharmaceuticals, Inc., assignee. Methods of treating metabolic disorders and cardiovascular disease with inhibin subunit beta E (INHBE) inhibitors and detection of INHBE variants. patent US20220184114. patent application US2021-17549692. 2022-06-16.

[304] Ahmad O, Försti A. The complementary roles of genome-wide approaches in identifying genes linked to an inherited risk of colorectal cancer. Hered Cancer Clin Pract. 2023;21(1):1.

[305] Rajagopal VM, Watanabe K, Mbatchou J, et al. Rare coding variants in CHRNB2 reduce the likelihood of smoking. Nat Genet. 2023;55(7):1138-1148.

[306] Darrah RJ, Jacono FJ, Joshi N, et al. AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations. J Cyst Fibros. 2019;18(1):127-134.

[307] Crosby J, Peloso GM, Auer PL, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371(1):22-31.

[308] Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371(1):32-41.

[309] Salem RM, Todd JN, Sandholm N, et al. Genome-wide association study of diabetic kidney disease highlights biology involved in glomerular basement membrane collagen. J Am Soc Nephrol. 2019;30(10):2000-2016.

[310] Emdin CA, Khera AV, Chaffin M, et al. Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. Nat Commun. 2018;9(1):1613.

[311] Agamah FE, Mazandu GK, Hassan R, et al. Computational/in silico methods in drug target and lead prediction. Brief Bioinform. 2020;21(5):1663-1675.

[312] Pun FW, Ozerov IV, Zhavoronkov A. AI-powered therapeutic target discovery. Trends Pharmacol Sci. 2023;44(9):561-572.

[313] Sarkar C, Das B, Rawat VS, et al. Artificial intelligence and machine learning technology driven modern drug discovery and development. Int J Mol Sci. 2023;24(3):2026.

[314] Modell AE, Lim D, Nguyen TM, Sreekanth V, Choudhary A. CRISPR-based therapeutics: current challenges and future applications. Trends Pharmacol Sci. 2022;43(2):151-161.

RIGHTS & PERMISSIONS

2024 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.