pulmoПульмонологияPULMONOLOGIYA0869-01892541-9617Scientific and Practical Journal “PULMONOLOGIYA” LLC10.18093/0869-0189-2021-31-2-226-236pulmo-2331Research ArticleОБЗОРЫREVIEWТаргетная терапия при муковисцидозеTargeted therapy for cystic fibrosishttps://orcid.org/0000-0002-3133-8018КуцевС. И.KutsevS. I.

Куцев Сергей Иванович – д. м. н., профессор, член-корр. Российской академии наук, директор.

115478, Москва, ул. Москворечье, 1; тел.: (499) 612-00-37

Sergey I. Kutsev, Doctor of Medicine, Professor, Corresponding Member of Russian Academy of Sciences, Director.

ul. Moskvorech’e 1, Moscow, 1115478, Russia; tel.: (499) 612-00-37

mgnc@med-gen.ruhttps://orcid.org/0000-0002-7246-5144ИжевскаяВ. Л.IzhevskayaV. L.

Ижевская Вера Леонидовна – д. м. н., заместитель директора по научной работе.

115478, Москва, ул. Москворечье, 1; тел.: (495) 324-15-34

Vera L. Izhevskaya, Doctor of Medicine, Deputy Director for Science.

ul. Moskvorech’e 1, Moscow, 1115478, Russia; tel.: (495) 324-15-34

izhevskaya@med-gen.ruhttps://orcid.org/0000-0001-6395-0407КондратьеваЕ. И.KondratyevaE. I.

Кондратьева Елена Ивановна – д. м. н., профессор, руководитель научно-клинического отдела муковисцидоза.

115478, Москва, ул. Москворечье, 1; тел.: (495) 111-03-03

Elena I. Kondratyeva, Doctor of Medicine, Professor, Head of the Scientific and Clinical Department of Cystic Fibrosis.

ul. Moskvorech’e 1, Moscow, 1115478, Russia; tel.: (495) 111-03-03

elenafpk@mail.ruФедеральное государственное бюджетное научное учреждение «Медико-генетический научный центр имени академика Н.П.Бочкова»РоссияFederal State Budgetary Scientific Institution “Research Center for Medical Genetics”Russian Federation202111042021312226236Copyright © Куцев С.И., Ижевская В.Л., Кондратьева Е.И., 20212021Куцев С.И., Ижевская В.Л., Кондратьева Е.И.Kutsev S.I., Izhevskaya V.L., Kondratyeva E.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.pulmonology.ru/pulm/article/view/2331

Базисная терапия муковисцидоза (МВ) направлена в настоящее время на замедление патологических процессов, связанных со снижением активности белка CFTR (муковисцидозного трансмембранного регулятора проводимости) в желудочно-кишечном тракте и респираторной системе. Панкреатическая недостаточность хорошо компенсируется заместительной терапией микросферическими ферментами, потреблением высококалорийной, богатой белками и жирами диетой. Постоянное лечение болезни легких, обусловленной МВ, нацелено на улучшение клиренса бронхиального дерева, подавление хронической бактериальной инфекции и местного хронического воспаления. Однако до 2012 г. терапия, исправляющая дефект гена или его продукта, не разработаны.

Целью обзора явился анализ данных литературы по применению модуляторов CFTR по их эффективности и безопасности, а также перспективы создания новых модуляторов для терапии МВ.

Материалы и методы

Материалы и методы. Использованы данные литературы (45 статей) по применению CFTR-модуляторов, а также данные международных сайтов.

Результаты

Результаты. Со времени открытия в 1989 г. гена CFTR описано > 2 000 мутаций или вариантов нуклеотидной последовательности гена CFTR (генетические варианты), препятствующие синтезу белка CFTR, его транспорту к апикальной мембране клетки или нарушающие его функцию в качестве канала анионов хлора. Хотя в настоящее время полная замена мутантного гена нормальной копией невозможна, идентифицированы малые молекулы, способные модифицировать мутантный белок CFTR таким образом, что его функция становится близкой к нормальной. Возможность терапевтических мероприятий определяется классом мутации. В клинической практике фармакологическое моделирование ионного транспорта возможно в настоящее время только с использованием модуляторов CFTR – корректоров и потенциаторов.

Зключение

Зключение. В обзоре приводятся определение этих групп препаратов и описание 4 зарегистрированных СFTR-модуляторов, включающих молекулы ивакфтор, лумакофтор, тезакафтор, элексакафтор. Приведены данные о перспективных разработках модуляторов следующего поколения и перспективы персонализированного подбора препаратов с использованием технологии кишечных органоидов.

The basic therapy of cystic fibrosis is currently aimed at slowing down the pathological processes associated with a decrease in the CFTR protein activity (cystic fibrosis transmembrane conductance regulator) in the gastrointestinal tract and the respiratory system. The pancreatic insufficiency is well compensated by replacement therapy with microsphere enzyme preparations and a high-calorie diet rich in proteins and fat. Chronic treatment of cystic fibrosis-related lung disease aims to improve the clearance of the bronchial tree, suppressing chronic bacterial infection and local chronic inflammation. However, no therapy was available to correct the defect in the gene or its product until 2012.

The aim was to analyze literature on CFTR modulators, including their efficacy and safety, and assess the potential for developing new modulators to treat cystic fibrosis.

Materials

Materials. The review included literature data (45 publications) on the use of CFTR modulators and international websites’ data.

Results

Results. Since the discovery of the CFTR gene in 1989, more than 2000 mutations or variants of the CFTR gene (hereinafter referred to as genetic variants) have been described. They interfere with the synthesis of the CFTR protein, its transport to the apical membrane of the cell, or disrupt its function as a channel for chloride anions. Although it is currently not possible to completely replace the mutant gene with a normal copy, small molecules have been identified that can modify the mutant CFTR protein and amend its function. The potential therapeutic measures are determined by class of the mutation. In clinical practice, pharmacological modeling of ion transport is currently possible only with the use of CFTR modulators: correctors and potentiators. The review defines these groups of drugs and describes 4 licensed CFTR modulators, including molecules of ivacaftor, lumacaftor, tezacaftor, elexacaftor. The data on the promising emerging next generation modulators and the prospects for the personalized selection of drugs using the assays on intestinal organoids are presented.

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The authors declare that there are no conflicts of interest present.