НОВЫЕ ПЕРСПЕКТИВЫ ФАРМАКОГЕНЕТИКИ МУКОВИСЦИДОЗА ПРИ КОМБИНИРОВАННОЙ ТЕРАПИИ (VX659-TЕЗАКАФТОР-ИВАКАФТОРОМ)

Яковлева О. А., Гойна-Кардасевич О. Ю., Жамба А. О., Дорошкевич И. А., Лушников Д. С.

ОБЗОРЫ ЛИТЕРАТУРЫ

Научная статья.

Статья посвящена проблеме генетических дефектов при муковисцидозе и наиболее успешным последним результатам исследования лечения муковисцидоза, на основе фармакогенетики, завершенного осенью 2018 года группой авторов (VX16-659-101 Study Group). С учетом различных генетических дефектов, наиболее оптимальным следует признать комбинированную терапию несколькими препаратами, с целью максимально возможного влияния и охвата этих генов дефектного белка CFTR. Доказано, что аддитивность VX-659 к тезакафтору и ивакафтору in vitro увеличивает биосинтез белка Phe508del CFTR в клетке и перенос на её поверхность. Клинические испытания подтверждают концепцию: влияние на восстановление функции белка CFTR Phe508del с помощью схемы тройной комбинации, приблизительно у 9 из 10 пациентов, которые содержат одну или две аллели Phe508del.

муковисцидоз, фармакогенетика, комбинированная терапия

1. Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet. 2015;16:45-56.
2. Elborn JS. Cystic fibrosis. Lancet. 2016;388:2519-31.
3. Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013;45:1160-7.
4. Gentzsch M, Mall MA. Ion channel modulators in cystic fibrosis. Chest. 2018;154:383-93.
5. Cystic Fibrosis Foundation Patient Registry. 2016 Annual data report. Bethesda, MD: Cystic Fibrosis Foundation, 2017.
6. Veit G, Avramescu RG, Chiang AN, Houck SA, Peters KW, Hong JS, et al. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Molecular Biology of the Cell. 2016;27(1):424-33.
7. Davies JC, Moskowitz SM, Brown C, Horsley A, Mall MA, McKone EF, et al. VX16-659-101 Study Group. VX-659–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018;379:1599-611.
8. Pettit RS, Fellner C. CFTR modulators for the treatment of cystic fibrosis. P T. 2014;39:500-11.
9. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA. 2009;106:18825-30.
10. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA. 2009;106:18825-30.
11. Luciani A, Villella VR, Esposito S, Gavina M, Russo I, Silano M, et al. Targeting autophagy as a novel strategy for facilitating the therapeutic action of potentiators on ΔF508 cystic fibrosis transmembrane conductance regulator. Autophagy. 2012;8:1657-72.
12. Yu H, Burton B, Huang CJ, Worley J, Cao D, Johnson JP , et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012;11:237-45.
13. Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187:1219-25.
14. Van Goor F, Yu H, Burton B, Hoffman BJ. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014;13:29-36.
15. Veit G, Avramescu RG, Perdomo D, Phuan PW, Bagdany M, Apaja PM, et al. Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression. SciTransl Med. 2014;6:246ra97.
16. Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, et al. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med. 2014;2:527-38.
17. Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, et al. Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373:220-31.
18. Taylor-Cousar JL, Munck A, McKone EF, Van der Ent CK, Moeller A, Simard C, et al. Tezacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017;377:2013-23.
19. Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, et al. Tezacaftor–ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377:2024-35.
20. Flume P, Lekstrom-Himes J, Fischer Biner R, Simard C, Downey DG, Zhou H, et al. A phase 3, open-label study of tezacaftor/ivacaftor (TEZ/IVA) therapy: interim analysis of pooled safety, and efficacy in patients homozygous for F508del-CFTR. J Cyst Fibros. 2018;17(3):64-5.
21. Flume P, Owen CA, Fischer Biner R, Lekstrom-Himes J, Simard C, Downey DG, et al. A phase 3, open-label study of tezacaftor/ivacaftor (TEZ/ IVA) therapy: interim analysis of pooled safety, and efficacy in patients heterozygous for F508del-CFTR and a residual function mutation. J Cyst Fibros. 2018;17(3):29.
22. Grootenhuis P, Van Goor F, Hadida S. Discovery and biological profile of next-generation CFTR correctors. Pediatr Pulmonol. 2016;51(45):263.
23. Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, et al. VX-445–tezacaftor–ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med. 2018;379:1612-20.
24. Amaral MD. Novel personalized therapies for cystic fibrosis: treating the basic defect in all patients. J Intern Med. 2015;277:155-66.
25. Marson FAL, Bertuzzo CS, Ribeiro JD. Personalized drug therapy in cystic fibrosis: from fiction to reality. Curr Drug Targets. 2015;16:1007-17.
26. Awatade NT, Uliyakina I, Farinha CM, Clarke LA, Mendes K, Sole A, et al. Measurements of functional responses in human primary lung cells as a basis for personalized therapy for cystic fibrosis. EBioMedicine. 2015;2:147-53.
27. Ren CL, Morgan RL, Oermann C, Resnick HE, Brady C, Campbell A, et al. Cystic Fibrosis Foundation pulmonary guidelines: use of cystic fibrosis transmembrane conductance regulator modulator therapy in patients with cystic fibrosis. Ann Am Thorac Soc. 2018;15:271-80. 

«Вестник проблем биологии и медицины» Выпуск 1 Том 1 (148), 2019 год, 75-80 страницы, код УДК 615.015.2:[616.24+616.3+616.53/.56]-002.17-008.9

10.29254/2077-4214-2019-1-1-148-75-80