Hereditary angioedema: modern approaches to modeling, diagnostics and therapy

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Hereditary angioedema is a rare but potentially life-threatening disease characterized by episodic swelling due to excessive bradykinin production.

This review discusses the main pathogenetic mechanisms of the disease and analyzes the main differences between types of hereditary angioedema with C1-inhibitor deficiency (types I and II) and with normal C1-inhibitor levels. The paper summarizes and systematizes the main biomarkers with diagnostic significance for hereditary angioedema, including the level and functional activity of C1-inhibitor, the concentration of complement system components (C4, C1r, C1s), as well as molecular genetic markers that allow verifying the disease type. Modern therapeutic strategies are presented, focusing both on the rapid relief of acute attacks using drugs that target the kallikrein-kinin system, and on preventive approaches that reduce the frequency, severity, and duration of recurrences. An important part of the review is the analysis of existing in vitro and in vivo models of hereditary angioedema, including cell systems and transgenic animal models used for the preclinical evaluation of the efficacy and safety of new therapeutic agents, as well as for a deeper understanding of the molecular and cellular mechanisms underlying the disease.

The presented analysis highlights the importance of integrating fundamental and applied research to develop personalized approaches for hereditary angioedema management and to improve patient prognosis.

About the authors

Veronika A. Parshina

National Research Center – Institute of Immunology Federal Medical-Biological Agency; Center for genetic reprogramming and gene therapy, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Author for correspondence.
Email: parshina.nicka@yandex.ru
ORCID iD: 0009-0001-7678-2489
SPIN-code: 1883-8361
Russian Federation, Moscow; Moscow

Olesya O. Koloskova

National Research Center – Institute of Immunology Federal Medical-Biological Agency

Email: oo.koloskova@nrcii.ru
ORCID iD: 0000-0003-3949-8582
SPIN-code: 1493-1160

MD, Cand. Sci. (Biology)

Russian Federation, Moscow

Maria V. Khodzhava

National Research Center – Institute of Immunology Federal Medical-Biological Agency; Center for genetic reprogramming and gene therapy, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: mchernobaeva@mail.ru
ORCID iD: 0009-0005-5140-1554
SPIN-code: 3046-8033

MD, Cand. Sci. (Pharmacy)

Russian Federation, Moscow; Moscow

Elena A. Latysheva

National Research Center – Institute of Immunology Federal Medical-Biological Agency

Email: ealat@mail.ru
ORCID iD: 0000-0002-1606-205X
SPIN-code: 2063-7973

MD, Dr. Sci. (Medicine)

Russian Federation, Moscow

Nadezda N. Shershakova

National Research Center – Institute of Immunology Federal Medical-Biological Agency; Center for genetic reprogramming and gene therapy, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

Email: nn.shershakova@nrcii.ru
ORCID iD: 0000-0001-6444-6499
SPIN-code: 7555-5925

MD, Dr. Sci (Biology)

Russian Federation, Moscow; Moscow

Musa R. Khaitov

National Research Center – Institute of Immunology Federal Medical-Biological Agency; Center for genetic reprogramming and gene therapy, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency; The Russian National Research Medical University named after N.I. Pirogov

Email: mr.khaitov@nrcii.ru
ORCID iD: 0000-0003-4961-9640
SPIN-code: 3199-9803

д-р мед. наук, профессор, академик РАН

Russian Federation, Moscow; Moscow; Moscow

References

  1. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027–1036. doi: 10.1056/NEJMcp0803977
  2. Ritter AMV, Silva S, de Paula R, et al. A real-world study of hereditary angioedema patients due to C1 inhibitor deficiency treated with danazol in the Brazilian Public Health System. Front Med. 2024;11:1343547. doi: 10.3389/fmed.2024.1343547 EDN: IZJJGN
  3. Santacroce R, D’Andrea G, Maffione AB, et al. The genetics of hereditary angioedema: a review. J Clin Med. 2021;10(9):2023. doi: 10.3390/jcm10092023 EDN: WUSGVC
  4. The US Hereditary Angioedema Association. Available from: https://www.haea.org/pages/p/what_is_hae
  5. Министерство здравоохранения Российской Федерации. Наследственный ангиоотек. Клинические рекомендации. Режим доступа: https://cr.minzdrav.gov.ru/view-cr/267_2
  6. Ghazi A, Grant JA. Hereditary angioedema: epidemiology, management, and role of icatibant. Biologics. 2013;7:103–113. doi: 10.2147/BTT.S27566
  7. Tutunaru CV, Ică OM, Mitroi GG, et al. Unveiling the complexities of hereditary angioedema. Biomolecules. 2024;14(10):1298. doi: 10.3390/biom14101298 EDN: MVOSRY
  8. Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet. 2012;379(9814):474–481. doi: 10.1016/S0140-6736(11)60935-5
  9. Sinnathamby ES, Issa PP, Roberts L, et al. Hereditary angioedema: diagnosis, clinical implications, and pathophysiology. Adv Ther. 2023;40(3):814–827. doi: 10.1007/s12325-022-02401-0 EDN: RKZMPM
  10. Bork K, Aygören-Pürsün E, Bas M, et al. Guideline: hereditary angioedema due to C1 inhibitor deficiency. Allergo J Int. 2019;28(1):16–29. doi: 10.1007/s40629-018-0088-5 EDN: HZCBIR
  11. Germenis AE, Speletas M. Genetics of hereditary angioedema revisited. Clin Rev Allergy Immunol. 2016;51(2):170–182. doi: 10.1007/s12016–016–8543-x EDN: KUOZTQ
  12. Gooptu B, Lomas DA. Conformational pathology of the serpins: themes, variations, and therapeutic strategies. Annu Rev Biochem. 2009;78:147–176. doi: 10.1146/annurev.biochem.78.082107.133320 EDN: LNSLPB
  13. Guryanova I. Congenital angioedema: molecular basis of formation, mechanisms of development, features of clinical manifestations, pathogenetic therapy. Laboratory Diagnostics. Eastern Europe. 2021;10(4). (In Russ.) doi: 10.34883/PI.2021.10.4.011 EDN: CERWMH
  14. Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema — the 2021 revision and update. Allergy. 2022;77(7):1961–1990. doi: 10.1111/all.15214 EDN: FOPZTW
  15. Lacuesta G, Betschel SD, Tsai E, Kim H. Angioedema. Allergy Asthma Clin Immunol. 2024;20(Suppl 3):65. doi: 10.1186/s13223-024-00934-3 EDN: FEFCSI
  16. Bors A, Csuka D, Varga L, et al. Less severe clinical manifestations in patients with hereditary angioedema with missense C1INH gene mutations. J Allergy Clin Immunol. 2013;131(6):1708–1711. doi: 10.1016/j.jaci.2012.11.015
  17. Simonovic I, Patston, PA. The native metastable fold of C1-inhibitor is stabilized by disulfide bonds. Biochim Biophys Acta. 2000;1481(1):97–102. doi: 10.1016/S0167-4838(00)00115-1 EDN: AICXRJ
  18. Verpy E, Couture-Tosi E, Eldering E, et al. Crucial residues in the carboxy-terminal end of C1 inhibitor revealed by pathogenic mutants impaired in secretion or function. J Clin Invest. 1995;95(1):350–359. doi: 10.1172/jci117663
  19. Vatsiou S, Zamanakou M, Loules G, et al. A novel deep intronic SERPING1 variant as a cause of hereditary angioedema due to C1-inhibitor deficiency. Allergol Int. 2020;69(3):443–449. doi: 10.1016/j.alit.2019.12.009 EDN: KUZMZM
  20. Hujová P, Souček P, Grodecká L, et al. Deep intronic mutation in SERPING1 caused hereditary angioedema through pseudoexon activation. J Clin Immunol. 2020;40(3):435–446. doi: 10.1007/s10875-020-00753-2 EDN: OGXHKI
  21. Banday AZ, Kaur A, Jindal AK, et al. An update on the genetics and pathogenesis of hereditary angioedema. Genes Dis. 2019;7(1):75–83. doi: 10.1016/j.gendis.2019.07.002 EDN: KUQLJU
  22. Chen LM, Chung P, Chao S, et al. Differential regulation of kininogen gene expression by estrogen and progesterone in vivo. Biochim Biophys Acta. 1992;1131(2):145–151. doi: 10.1016/0167-4781(92)90069-c
  23. Madeddu P, Emanueli C, Song Q, et al. Regulation of bradykinin B2-receptor expression by oestrogen. Br J Pharmacol. 1997;121(8):1763–1769. doi: 10.1038/sj.bjp.0701255
  24. Zhang Y, Tortorici MA, Pawaskar D, et al. Exposure-response model of subcutaneous C1-inhibitor concentrate to estimate the risk of attacks in patients with hereditary angioedema. CPT Pharmacometrics Syst Pharmacol. 2018;7(3): 158–165. doi: 10.1002/psp4.12271
  25. Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun. 2006;343(4):1286–1289. doi: 10.1016/j.bbrc.2006.03.092
  26. Bork K, Gül D, Hardt J, Dewald G. Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course. Am J Med. 2007;120(11):987–992. doi: 10.1016/j.amjmed.2007.08.021
  27. Bork K, Wulff K, Steinmüller-Magin L, et al. Hereditary angioedema with a mutation in the plasminogen gene. Allergy. 2018;73(2):442–450. doi: 10.1111/all.13270 EDN: YCXAOD
  28. Dewald G. A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun. 2018;498(1):193–198. doi: 10.1016/j.bbrc.2017.12.060
  29. Bafunno V, Firinu D, D’Apolito M, et al. Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. J Allergy Clin Immunol. 2018;141(3):1009–1017. doi: 10.1016/j.jaci.2017.05.020
  30. D’Apolito M, Santacroce R, Colia AL, et al. Angiopoietin-1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema. Clin Exp Allergy. 2019;49(5):626–635. doi: 10.1111/cea.13349
  31. Cagini N, Lopez Veronez C, Franca Azevedo B, et al. In silico analysis of alterations in ANGPT1 gene supports a new pathway responsible to mediate hereditary angioedema in Brazilian patients with no mutations in SERPING1 and F12 genes. J Allergy Clin Immunol. 2018;141(2):AB46. doi: 10.1016/j.jaci.2017.12.150
  32. Bork K, Wulff K, Rossmann H, et al. Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin. Allergy. 2019;74(12):2479–2481. doi: 10.1111/all.13869
  33. Ariano A, D’Apolito M, Bova M, et al. A myoferlin gain-of-function variant associates with a new type of hereditary angioedema. Allergy. 2020; 75(11):2989–2992. doi: 10.1111/all.14454 EDN: PJRHIB
  34. Bork K, Wulff K, Möhl BS, et al. Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation. J Allergy Clin Immunol. 2021;148(4):1041–1048. doi: 10.1016/j.jaci.2021.01.011 EDN: AMMMOR
  35. D’Apolito M, Santacroce R, Vazquez DO, et al. DAB2IP associates with hereditary angioedema: insights into the role of VEGF signaling in HAE pathophysiology. J Allergy Clin Immunol. 2024;154(3):698–706. doi: 10.1016/j.jaci.2024.05.017 EDN: FCOXFK
  36. Vincent D, Parsopoulou F, Martin L, et al. Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency. J Allergy Clin Immunol Glob. 2024;3(2):100223. doi: 10.1016/j.jacig.2024.100223 EDN: OTAVGB
  37. Porebski G, Kwitniewski M, Reshef A. Biomarkers in hereditary angioedema. Clin Rev Allergy Immunol. 2021;60(3):404–415. doi: 10.1007/s12016-021-08845-6 EDN: NOMJCU
  38. Csuka D, Füst G, Farkas H, Varga L. Parameters of the classical complement pathway predict disease severity in hereditary angioedema. Clin Immunol. 2011;139(1):85–93. doi: 10.1016/j.clim.2011.01.003
  39. Germenis AE, Cicardi M. Driving towards precision medicine for angioedema without wheals. J Autoimmun. 2019;104:102312. doi: 10.1016/j.jaut.2019.102312
  40. Betschel S, Badiou J, Binkley K, et al. Correction to: The International/Canadian Hereditary Angioedema Guideline. Allergy Asthma Clin Immunol. 2020;16:33. doi: 10.1186/s13223-020-00430-4
  41. Veronez CL, Aabom A, Martin RP, et al. Genetic variation of kallikrein-kinin system and related genes in patients with hereditary angioedema. Front Med. 2019;6:28. doi: 10.3389/fmed.2019.00028
  42. Cugno M, Zanichelli A, Bellatorre AG, et al. Plasma biomarkers of acute attacks in patients with angioedema due to C1-inhibitor deficiency. Allergy. 2009; 64(2):254–257. doi: 10.1111/j.1398-9995.2008.01859.x
  43. Bova M, Suffritti C, Bafunno V, et al. Impaired control of the contact system in hereditary angioedema with normal C1-inhibitor. Allergy. 2020;75(6):1394–1403. doi: 10.1111/all.14160 EDN: HZGTHY
  44. Salemi M, Mandalà V, Muggeo V, et al. Growth factors and IL-17 in hereditary angioedema. Clin Exp Med. 2016;16(2):213–218. doi: 10.1007/s10238-015-0340-y EDN: OKRMRP
  45. Anderson J, Soteres D, Mellor J, et al. Physician- and patient-reported outcomes by hereditary angioedema type: Data from a real-world study. Allergy Asthma Proc. 2024;45(4):247–254. doi: 10.2500/aap.2024.45.240021 EDN: DGJIPK
  46. Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema — the 2021 revision and update. Allergy. 2022;77(7):1961–1990. doi: 10.1111/all.15214 EDN: FOPZTW
  47. Ionis announces FDA acceptance of New Drug Application for donidalorsen for prophylactic treatment of HAE. Available from: https://ir.ionis.com/news-releases/news-release-details/ionis-announces-fda-acceptance-new-drug-application-donidalorsen
  48. Pharmaceutical technology. Available from: https://www.pharmaceutical-technology.com/news/fda-kalvistas-ekterly-hereditary-angioedema/
  49. Marceau F, Bachelard H, Charest-Morin X, et al. In vitro modeling of bradykinin-mediated angioedema states. Pharmaceuticals (Basel). 2020;13(9):201. doi: 10.3390/ph13090201 EDN: COWUSH
  50. Haslund D, Ryø LB, Seidelin Majidi S, et al. Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema. J Clin Invest. 2019;129(1):388–405. doi: 10.1172/JCI98869
  51. Jin G, Kawsar HI, Hirsch SA, et al. An antimicrobial peptide regulates tumor-associated macrophage trafficking via the chemokine receptor CCR2, a model for tumorigenesis. PloS One. 2010;5(6):e10993. doi: 10.1371/journal.pone.0010993 EDN: NYLEZR
  52. Ravi M, Paramesh V, Kaviya SR, et al. 3D cell culture systems: advantages and applications. J Cell Physiol. 2015;230(1):16–26. doi: 10.1002/jcp.24683
  53. Dembélé P, Garnier O, Martin DK, Vilgrain I. Microtumor spheroids provide a model for studying molecules involved in vascular organization: an illustrative study for VE-cadherin. Anticancer Res. 2022;42(10):4689–4700. doi: 10.21873/anticanres.15973 EDN: HBNEEE
  54. Paloschi V, Sabater-Lleal M, Middelkamp H, et al. Organ-on-a-chip technology: a novel approach to investigate cardiovascular diseases. Cardiovasc Res. 2021;117(14):2742–2754. doi: 10.1093/cvr/cvab088 EDN: HEKKCF
  55. Lim J, Fang HW, Bupphathong S, PC, Yeh CE, Huang W, et al. The edifice of vasculature-on-chips: a focused review on the key elements and assembly of angiogenesis models. ACS Biomater Sci Eng. 2024;10(6):3548–3567. doi: 10.1021/acsbiomaterials.3c01978 EDN: FLOGSA
  56. Radermacher C, Rohde A, Kucikas V, et al. Various hydrogel types as a potential in vitro angiogenesis model. Gels. 2024;10(12):820. doi: 10.3390/gels10120820 EDN: KZRAKT
  57. Han ED, MacFarlane RC, Mulligan AN, et al. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest. 2002;109(8):1057–1063. doi: 10.1172/JCI14211
  58. Bupp S, Whittaker M, Lehtimaki M, et al. A novel murine in vivo model for acute hereditary angioedema attacks. Sci Rep. 2021;11(1):15924. doi: 10.1038/s41598-021-95125-0 EDN: ZYJJQX
  59. Qiu T, Chiuchiolo MJ, Whaley AS, et al. Gene therapy for C1 esterase inhibitor deficiency in a Murine model of hereditary angioedema. Allergy. 2019;74(6): 1081–1089. doi: 10.1111/all.13582
  60. Kokoye Y, Ivanov I, Cheng Q, et al. A comparison of the effects of factor XII deficiency and prekallikrein deficiency on thrombus formation. Thromb Res. 2016;140:118–124. doi: 10.1016/j.thromres.2016.02.020 EDN: WSLBIJ

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2025 ABV-press

Согласие на обработку персональных данных

 

Используя сайт https://journals.rcsi.science, я (далее – «Пользователь» или «Субъект персональных данных») даю согласие на обработку персональных данных на этом сайте (текст Согласия) и на обработку персональных данных с помощью сервиса «Яндекс.Метрика» (текст Согласия).