Login Register Cart 0
Generic placeholder image

Current Drug Safety

Editor-in-Chief

ISSN (Print): 1574-8863
ISSN (Online): 2212-3911

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Perspective

Molecular Fingerprinting by Single Cell Clone Analysis in Adverse Drug Reaction (ADR) Assessment

Author(s): Anjan K. Banerjee *

Volume 17, Issue 1, 2022

Published on: 27 July, 2021

Page: [1 - 6] Pages: 6

DOI: 10.2174/1574886316666210727150415

Abstract

Causality assessment for idiosyncratic ADRs mainly relies on epidemiology, signal detection and less often on proven or plausible mechanistic evidence of the drug at a cellular or organ level. Distinct clones of cells can exist within organs of individual patients, some conferring susceptibility to well-recognised Adverse Drug Reactions (ADRs). Recent advances in molecular biology have allowed the development of single-cell clonal techniques, including single-cell RNA sequencing (scRNA-seq) to molecularly fingerprint ADRs and distinguish between distinct clones of cells within organs in individuals, which may confer differing susceptibilities to ADRs. ScRNA- seq permits molecular fingerprinting of some serious ADRs, mainly in the skin, through the identification of Directly Expressed Genes (DEG) of interest within specific clones. Overexpressed DEGs provide an opportunity for targeted treatment strategies to be developed. scRN A-seq could be applied to a number of other ADRs involving tissues that can be biopsied/sampled (including skin, liver, kidney, blood, stem cells) as well as providing a molecular basis for rapid screening of potential therapeutic candidates, which may not otherwise be predictable from a class of toxicity/organ involvement. A framework for putative assessment for ADRs using scRNA-seq is proposed as well as speculating on potential regulatory implications for pharmacovigilance and drug development. Molecular fingerprinting of ADRs using scRNA-seq may allow better targeting for enhanced pharmacovigilance and risk minimisation measures for medicines with appropriate benefit-risk profiles, although cost-effectiveness and other factors, such as frequency/severity of individual ADRs and population differences, will still be relevant.

Keywords: Adverse drug reactions (ADRs), directly expressed genes, RNA sequencing, epidemiology, fingerprinting, single cell clone.

Next »
Graphical Abstract

[1]
Uetrecht J, Naisbitt DJ. Idiosyncratic adverse drug reactions: Current concepts. Pharmacol Rev 2013; 65(2): 779-808.
[http://dx.doi.org/10.1124/pr.113.007450] [PMID: 23476052]
[2]
Lauschke VM, Zhou Y, Ingelman-Sundberg M. Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity. Pharmacol Ther 2019; 197: 122-52.
[http://dx.doi.org/10.1016/j.pharmthera.2019.01.002] [PMID: 30677473]
[3]
Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008; 358(6): 568-79.
[http://dx.doi.org/10.1056/NEJMoa0706135] [PMID: 18256392]
[4]
Chen P, Lin JJ, Lu CS, et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med 2011; 364(12): 1126-33.
[http://dx.doi.org/10.1056/NEJMoa1009717] [PMID: 21428768]
[5]
Monshi MM, Faulkner L, Gibson A, et al. Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury. Hepatology 2013; 57(2): 727-39.
[http://dx.doi.org/10.1002/hep.26077] [PMID: 22987284]
[6]
Kim S-H, Saide K, Farrell J, et al. Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury. Hepatology 2015; 62(3): 887-99.
[http://dx.doi.org/10.1002/hep.27912] [PMID: 25998949]
[7]
Usui T, Tailor A, Faulkner L, et al. HLA-A*33:03-restricted activation of ticlopidine-specific T-Cells from human donors. Chem Res Toxicol 2018; 31(10): 1022-4.
[http://dx.doi.org/10.1021/acs.chemrestox.8b00163] [PMID: 30179004]
[8]
Shalek AK, Benson M. Single-cell analyses to tailor treatments. Sci Transl Med 2017; 9(408): eaan4730.
[http://dx.doi.org/10.1126/scitranslmed.aan4730] [PMID: 28931656]
[9]
Gierahn TM, Wadsworth MH II, Hughes TK, et al. Seq-Well: Portable, low-cost RNA sequencing of single cells at high throughput. Nat Methods 2017; 14(4): 395-8.
[http://dx.doi.org/10.1038/nmeth.4179] [PMID: 28192419]
[10]
Stewart BJ, Ferdinand JR, Clatworthy MR. Using single-cell technologies to map the human immune system - implications for nephrology. Nat Rev Nephrol 2020; 16(2): 112-28.
[http://dx.doi.org/10.1038/s41581-019-0227-3] [PMID: 31831877]
[11]
Duong TA, Valeyrie-Allanore L, Wolkenstein P, Chosidow O. Severe cutaneous adverse reactions to drugs. Lancet 2017; 390(10106): 1996-2011.
[http://dx.doi.org/10.1016/S0140-6736(16)30378-6] [PMID: 28476287]
[12]
Kim D, Kobayashi T, Voisin B, et al. Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: A case report. Nat Med 2020; 26(2): 236-43.
[http://dx.doi.org/10.1038/s41591-019-0733-7] [PMID: 31959990]
[13]
Mack MR, Kim BS. A precision medicine-based strategy for a severe adverse drug reaction. Nat Med 2020; 26(2): 167-8.
[http://dx.doi.org/10.1038/s41591-020-0756-0] [PMID: 32015558]
[14]
Miyagawa F, Nakamura Y, Miyashita K, et al. Preferential expression of CD134, an HHV-6 cellular receptor, on CD4T cells in drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS). J Dermatol Sci 2016; 83(2): 151-4.
[http://dx.doi.org/10.1016/j.jdermsci.2016.05.001] [PMID: 27174092]
[15]
Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA 2005; 102(11): 4134-9.
[http://dx.doi.org/10.1073/pnas.0409500102] [PMID: 15743917]
[16]
Phillips EJ. New strategies to predict and prevent serious immunologically mediated adverse drug reactions. Trans Am Clin Climatol Assoc 2018; 129: 74-87.
[PMID: 30166701]
[17]
Zhang B, Huang K, Zhu L, Luo Y, Xu W. Precision toxicology based on single cell sequencing: An evolving trend in toxicological evaluations and mechanism exploration. Arch Toxicol 2017; 91(7): 2539-49.
[http://dx.doi.org/10.1007/s00204-017-1971-4] [PMID: 28451740]
[18]
Roden DM, McLeod HL, Relling MV, et al. Pharmacogenomics. Lancet 2019; 394(10197): 521-32.
[http://dx.doi.org/10.1016/S0140-6736(19)31276-0] [PMID: 31395440]
[19]
Kim KT, Lee HW, Lee HO, et al. Application of single-cell RNA sequencing in optimizing a combinatorial therapeutic strategy in metastatic renal cell carcinoma. Genome Biol 2016; 17: 80.
[http://dx.doi.org/10.1186/s13059-016-0945-9] [PMID: 27139883]
[20]
Legge SE, Walters JTR. Genetics of clozapine-associated neutropenia: Recent advances, challenges and future perspective. Pharmacogenomics 2019; 20(4): 279-90.
[http://dx.doi.org/10.2217/pgs-2018-0188] [PMID: 30767710]
[21]
Karnes JH. Pharmacogenetics to prevent heparin-induced thrombocytopenia: What do we know? Pharmacogenomics 2018; 19(18): 1413-22.
[http://dx.doi.org/10.2217/pgs-2018-0147] [PMID: 30398086]
[22]
Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med 2007; 357(6): 580-7.
[http://dx.doi.org/10.1056/NEJMra066469] [PMID: 17687133]
[23]
D’Avolio A, Cusato J, De Nicolò A, Allegra S, Di Perri G. Pharmacogenetics of ribavirin-induced anemia in HCV patients. Pharmacogenomics 2016; 17(8): 925-41.
[http://dx.doi.org/10.2217/pgs.16.22] [PMID: 27248282]
[24]
Medina PJ, Sipols JM, George JN. Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr Opinion Haematol 2001; 8: 286-93.
[25]
Kaliyaperumal K, Grove JI, Delahay RM, Griffiths WJH, Duckworth A, Aithal GP. Pharmacogenomics of drug-induced liver injury (DILI): Molecular biology to clinical applications. J Hepatol 2018; 69(4): 948-57.
[http://dx.doi.org/10.1016/j.jhep.2018.05.013] [PMID: 29792895]
[26]
Garon SL, Pavlos RK, White KD, Brown NJ, Stone CA Jr, Phillips EJ. Pharmacogenomics of off-target adverse drug reactions. Br J Clin Pharmacol 2017; 83(9): 1896-911.
[http://dx.doi.org/10.1111/bcp.13294] [PMID: 28345177]
[27]
Pirmohamed M, Park K. Mechanism of clozapine-induced agranulocytosis : Current status of research and implications for drug development. CNS Drugs 1997; 7(2): 139-58.
[http://dx.doi.org/10.2165/00023210-199707020-00005] [PMID: 23338132]
[28]
Chambers D, Carew A, Lukowski S, Powell J. Molecular techniques for respiratory diseases: Transcriptonomics and single cell RNA sequencing. Respirology 2019; 24: 29-36.
[http://dx.doi.org/10.1111/resp.13412] [PMID: 30264869]
[29]
Villani A-C, Satija R, Reynolds G, et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science 2017; 356(6335): eaah4573.
[http://dx.doi.org/10.1126/science.aah4573] [PMID: 28428369]
[30]
Kang HM, Subramaniam M, Targ S, et al. Multiplexed droplet single-cell RNA-sequencing using natural genetic variation. Nat Biotechnol 2018; 36(1): 89-94.
[http://dx.doi.org/10.1038/nbt.4042] [PMID: 29227470]

Rights & Permissions Print Cite
Article Metrics
30
1
© 2024 Bentham Science Publishers | Privacy Policy