In 2025, the Scientific and Clinical Department of Cystic Fibrosis of the Federal State Budgetary Scientific Institution “Research Centre for Medical Genetics” of the Ministry of Science and Higher Education of the Russian Federation celebrates its 35th anniversary.

   The aim of this publication was to demonstrate various areas of research conducted by specialists of the Cystic Fibrosis Department over the past 5 years, and some of their results.

   Results. Over 5 years, the research findings have been presented and published in 150 articles, 4 monographs, 3 national guidelines, 4 clinical guidelines, 6 candidate theses, and 1 doctoral thesis.

   Conclusion. The main achievements in organizing medical care for patients with CF and other orphan diseases in the Russian Federation were demonstrated.

   Cystic fibrosis (CF) is an autosomal recessive disorder caused by dysfunction of the CF transmembrane conductance regulator (CFTR) protein that can manifest at birth and progresses throughout life. CF results in multisystem disease with significantly reduced life expectancy.

   The aim of the review was to analyze the use of the CFTR modulator elexacaftor (ELX) / tezacaftor (TEZ) / ivacaftor (IVA) to justify the use of the new-generation modulator vanzacaftor (VNZ) / TEZ / deitivacaftor (D-IVA) and evaluate its efficacy.

   Results. We analyzed 35 scientific publications on CF and its targeted therapy and described the efficacy and safety of the VNZ/TEZ/D-IVA combination in patients with CF (n = 1,049) according to the phase III studies.

   Conclusion. VNZ/TEZ/D-IVA is a next generation CFTR modulator with increased potential to further improve clinical outcomes and further enhance long-term outcomes by restoring normal CFTR function in a larger number of CF patients. Additionally, VNZ/TEZ/D-IVA may improve treatment convenience for patients and caregivers.

   Polymorphism of genes involved in drug metabolism is one of the most common inherited risk factors associated with adverse drug reactions.

   The aim of the study was to study the effect of the polymorphism of genes involved in the phase 1 of xenobiotic biotransformation on the efficacy and safety of CFTR modulator therapy in cystic fibrosis, taking into account the complications, in order to optimize therapy.

   Methods. The study included 301 patients with the average age of 11.1 ± 3.8 years who received lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor in 2022–2024. Gene polymorphism was investigated for the following enzymes involved in the phase I of the drug metabolism: CYP2C9*3 (rs1057910; c.1075A>C; I359L), CYP2C9*2 (rs1799853; c.430 C>T; R144C), CYP2C19*2 (rs4244285; c.681G>A), CYP2C19*3 (rs4244285; c.681G>A), (rs4986893; c.636G>A; W212X), CYP2D6*4 (rs3892097; 1846G>A), CYP3A4*3 (rs4986910; M445T; c.1334 T>C), and CYP3A4*1B (rs2740574; c.-392C>T). The study was performed by PCR followed by RFLP analysis (restriction fragment length polymorphism) or AFLP analysis (amplified fragment length polymorphism).

   Results. Patients with the GG genotype of the CYP2D6*4 polymorphic variant of the CYP2D6 gene showed better weight gain after one year of therapy with CFTR modulators (p = 0.048). Patients with the AC genotype of the CYP2C9*3 polymorphic variant of the CYP2C9 gene demonstrated higher weight, height, and BMI before and one year after the therapy (p < 0.05), as well as better height gain over time (p = 0.010) compared to the carriers of the AA genotype, which indicates a higher efficacy of the targeted therapy in the AC genotype carriers. Patients with the GG genotype of the CYP2D6*4 polymorphic variant of the CYP2D6 gene and the AA genotype of the CYP2C19*2 polymorphic variant of the CYP2C19 gene more often had side effects and elevated serum liver transaminases. Patients with cirrhosis were more likely to have elevated transaminases and adverse events during the targeted therapy compared to the patients without any liver disease. Patients with a history of meconium ileus had lower FVC values after one year of therapy, higher ALT before/after therapy, and higher AST after therapy, and also showed better annual height gain during CFTR modulator therapy (p < 0.05).

   Conclusion. Determination of the genotype of polymorphisms CYP2C9*3 of the CYP2C9 gene, CYP2C19*2 of the CYP2C19 gene, and CYP2D6*4 of the CYP2D6 gene may be important for predicting the efficacy and safety (toxic effects on the liver) of targeted therapy for cystic fibrosis.

   CFTR modulators significantly improve clinical parameters and quality of life in people with cystic fibrosis (CF), but the effect of this treatment on the microbial profile of the respiratory tract has not been sufficiently studied.

   The aim. To assess changes in the microbial profile and clinical characteristics in adult CF patients during targeted therapy, to determine the correlation of these parameters with the duration of CFTR modulators treatment.

   Methods. The study included data on patients over 18 years of age from the national registry of patients with cystic fibrosis for 2021 – 2023. Data on microbiological, functional and anthropometric parameters of patients, as well as information on the use of CFTR modulators and antibiotics were analyzed.

   Results. The study included 1 141 adult patients, the average age was 25.32 years, the proportion of men was 50.74 %. CFTR modulators were taken by 450 patients. Only in this group was a significant improvement in forced expiratory volume in the first second (p < 0.001) and an increase in body mass index observed in 2021 – 2023. Pseudomonas aeruginosa is the dominant pathogen, most often in the form of chronic infection. The groups by the dominant pathogen remained stable; the change in groups in 283 of 1,141 patients was not associated with the use of CFTR modulators or its duration. At the beginning of therapy with CFTR modulators (less than one year), an increase in the number of patients receiving oral antibacterial therapy was noted. With a longer use of targeted therapies, the number of courses of antibacterial therapy decreases.

   Conclusion. According to the national registry of patients with cystic fibrosis for 2021 – 2023, the number of adults receiving CFTR modulators is increasing. Targeted therapy significantly improves respiratory function and nutritional status, but the microbiological profile of the respiratory tract of patients over 18 years of age did not change in the first years of treatment.

   In the Russian Federation, patients with cystic fibrosis (CF) under 19 years of age receive targeted therapy with two drugs: lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor. Currently, a large volume of information has accumulated regarding possible adverse drug reactions (ADRs) during long-term targeted therapy in children with CF.

   The aim of the study was to investigate the ADR profile associated with long-term use of CFTR modulators in children with CF.

   Methods. Data on the targeted therapy were taken from the Russian registry of CF patients (2021 – 2024). The data of 392 patients at the start of therapy with lumacaftor/ivacaftor, 196 patients after 1 year, and 36 patients after 2 years were analyzed. The data of 220 patients at the start of therapy with elexacaftor/tezacaftor/ivacaftor, 214 patients after 1 year, and 43 patients after 2 years were analyzed. Early adverse reactions were assessed within 30 days from the start of therapy. Change in the adverse reaction profile was assessed after 360 and 720 days.

   Results. The number of adverse reactions in patients receiving lumacaftor/ivacaftor was 51.27 % for 1 month. It decreased more than 2-fold (20.4 %) by the end of the 1st year (p1–2 < 0.001) due to a decrease in the number of patients with cough, shortness of breath, elevated alanine aminotransferase (ALT) / aspartate aminotransferase (AST) levels, and diarrhea. After 2 years, the incidence of adverse reactions was 55.5 % (p2–3 < 0.001), the number of patients with subfebrile body temperature/fever increased (p2–3 < 0.001; p1–3 < 0.001), the rate of fatigue increased to 11.1 % (p2–3 = 0.029), and the rate of sleep disturbance increased (from 0.25% at the start to 11.1 % after 2 years of therapy; p1–3 < 0.001; p2–3 < 0.001). The average incidence of adverse reactions per patient was 2.27 ± 0.45 for lumacaftor/ivacaftor. The total incidence of ADRs with elexacaftor/tezacaftor/ivacaftor combination therapy was 48.2 % at the start, 19.6 % after 1 year (p1–2 < 0.001), and increased to 41.9 % after 2 years (p2–3 < 0.001) due to subfebrile body temperature/fever – from 1.9 to 6.9 % (p1–3 = 0.032), headache – from 2.3 to 11.6 % (p1–3 = 0.003), and fatigue – up to 13.9 % (p1–3 < 0.001; p2–3 = 0.002). The average incidence of ADRs per patient was 2.56 ± 0.71 with elexacaftor/tezacaftor/ivacaftor combination therapy. More ADRs were observed at the start of therapy with lumacaftor/ivacaftor compared to elexacaftor/tezacaftor/ivacaftor (p = 0.019). The frequency of elevated ALT/AST levels at the start of therapy with lumacaftor/ivacaftor was higher than for elexacaftor/tezacaftor/ivacaftor (p = 0.02). Rash was observed more often at the start of therapy with elexacaftor/tezacaftor/ivacaftor (p < 0.001), fatigue – at the start of lumacaftor/ivacaftor (p = 0.011). No difference in the ADR profile was found after 2 years of therapy.

   Conclusion. A higher number of ADRs was associated with lumacaftor/ivacaftor compared to elexacaftor/tezacaftor/ivacaftor. Over time, the main adverse drug reactions associated with respiratory and gastrointestinal symptoms resolve, but the number of patients complaining of fatigue, sleep disturbances, headaches, subfebrile temperature and fever increases, requiring active follow-up and adjustment of the therapy if necessary.

   In recent years, new drugs have been discovered to treat cystic fibrosis (CF), which directly target the primary defects of CFTR: correctors and potentiators.

   The aim was to evaluate the efficacy and safety of Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in children with CF aged 2 – 6 years in routine clinical practice.

   Methods. An open observational study enrolled patients diagnosed with CF aged 2 – 6 years (n = 8) who received elexacaftor/tezacaftor/ivacaftor and ivacaftor. The following parameters were evaluated over time: height, weight, body mass index (BMI), sweat chlorides, fecal elastase 1, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and glucose.

   Results. During therapy, there was an absolute decrease in the level of sweat chlorides from an average of 110.12 (SD – 10.35) mmol/L at visit 1 to 61.37 (SD – 9.15) mmol/L (p < 0.05) after 1 month of treatment. The sweat chlorides level at visit 6 was 52.62 (SD – 7.67) mmol/l (p < 0.05). The body weight increased from 15.5 kg (SD – 2.4) to 18.8 kg (SD – 1.36) (p < 0.05), height – from 99.88 cm to 110.37 cm. The BMI varied from 15.76 (SD – 0.44) kg/m² at baseline to 16.26 (SD – 0.23) by the 9^th month (p < 0.05) and 15.02 (SD – 0.13) kg/m² by the 12^th month of follow-up (p > 0.05). The level of fecal
elastase-1 grew from 143.14 μg/g of stool (SD – 77.12) to 240.3 μg/g of stool (SD – 77.31) at 6 months after the start of therapy, and was 232.7 μg/g of stool (SD – 128.58) by the 12^th month of follow-up (p > 0.05). Undesirable side effects were mild and did not require discontinuation of the drug.

   Conclusion. For the first time in Russia, an open observational study was conducted as part of routine clinical practice to evaluate the effectiveness and safety of targeted therapy using elexacaftor/tezacaftor/ivacaftor and ivacaftor in children aged 2 – 6 years. Clinical and laboratory efficacy and safety have been demonstrated during 12 months of continuous follow-up.

   Early diagnosis of cystic fibrosis (CF) using neonatal screening (NS) allows for early initiation of therapy and regular follow-up.

   The aim of the study was to compare health indicators of 12–18-year-old children with CF in the Moscow region before and after the introduction of the NS in the Russian Federation.

   Methods. Patients (n = 63; age 12 – 18 years) with CF, genotype F508del/F508del, residents of the Moscow region, were divided into 2 groups: the diagnosis in patients of group 1 (n = 21) was established based on clinical manifestations before the introduction of the NS program in the Russian Federation (data from the CF patient registers for 2011 and 2012); the diagnosis in group 2 (n = 42) was based on the NS results (data from the CF patient register for 2022).

   Results. After the introduction of the NS, the median (Me) age at diagnosis decreased from 3.0 (0.5; 3.5) years in patients of group 1 to 0.2 (0.1; 0.4) years in group 2 (p = 0.001). A significant improvement in the parameters of external respiration function was noted in the 2^nd group: the Me (Q1 – Q3) of the forced vital capacity was 89.0 % (80.0; 100.0) predicted vs. 78.0 % (63.7; 89.9) predicted in the 1^st group (p = 0.015), the forced expiratory volume in 1 second was 87.0 % (73.0; 99.0) predicted in the group 2 vs 64.0 % (52.1; 82.0) predicted in group 1 (p = 0.004). A decrease in the incidence of chronic Pseudomonas aeruginosa infection was revealed: 6 % (28.6) patients in group 1 vs 1 (2.4 %) in group 2 (p = 0.002). No cases of chronic Burkholderia cepacia complex infection were registered in group 2, while in group 1 there were 23.8 % of such patients (p = 0.001). The use of inhaled antibacterial drugs (ABD) decreased from 71.4 % in 2011 to 46.3 % in 2022 (p = 0.049), intravenous antibacterial therapy from 90.5 % to 22.0 % (p < 0.001) and oral ABD (p = 0.005). The use of ursodeoxycholic acid decreased (p = 0.032). The number of patients with chronic polypous rhinosinusitis decreased from 57.1 % to 31.0 % (p = 0.045).

   Conclusion. NS for CF is an effective tool for improving the quality of medical care for patients with CF. Early diagnosis of the disease and follow-up from birth allow achieving target values of physical development and pulmonary function in adolescents. Our findings confirm the need for further development of screening programs and the introduction of modern treatment methods.

   Most of the known pathogenic variants of the CFTR gene are rare. Studying these variants allows us to gain new knowledge about the pathogenesis of cystic fibrosis, assess the variability of its manifestations among patients, and optimize therapeutic approaches.

   The aim was to comprehensively study a rare variant of the CFTR gene G1047S (c.3139G>A, p.(Gly1047Ser)) in two siblings, including a description of the clinical picture, functional assessment of the CFTR channel ex vivo by determining the intestinal current measurement (ICM) and the forskolin-induced swelling (FIS) assay of the effect of CFTR modulators in vitro in the intestinal organoids.

   Methods. The case history was presented. The ICM was used to study membrane channels of the intestinal epithelium. The FIS assay in the intestinal organoids of the patients was used to assess the sensitivity of the G1047S variant to ivacaftor, lumacaftor, tezacaftor, and elexacaftor.

   Results. The missense variant G1047S is pathogenic but “mild” since the residual CFTR function is observed. The results of functional tests are consistent with the clinical picture: the siblings have pancreatic sufficiency, no nutritional deficiency, and a “mild” course of the disease. The ivacaftor + tezacaftor + elexacaftor therapy can be recommended for patients with the G1047S variant since the intestinal organoid model shows restoration of CFTR functional activity.

   Conclusion. The G1047S variant is “mild”, but with lower sensitivity to known combination targeted drugs compared to F508del/F508del.

   Cystic fibrosis (CF) is a multi-organ disease, but its course and prognosis in most cases are determined by the pathology of the bronchopulmonary system. One of the most harmful pathogens for patients with CF is Burkholderia cepacia complex (Bcc). These are gram-negative bacteria characterized by high transmissibility and pathogenicity, as well as natural resistance to a wide range of antimicrobial drugs and rapid acquisition of resistance to new antibiotics. This seriously limits the therapeutic possibilities of eradication and treatment of Bcc, progressively reduces the lung function, and significantly limits the life expectancy of patients. A “cepacia syndrome” has also been described for Bcc – a rapidly increasing respiratory failure due to necrotizing pneumonia. Russia belongs to the countries with a relatively high Bcc prevalence of 5.5 %.

   The aim of the review was to analyze the literature data on the prevalence of Bcc in adult patients with CF in the Russian Federation, the impact of chronic Bcc infection on the course of CF and survival, including after lung transplantation, and the possibility of its eradication and treatment. Burkholderia cenocepacia ST709, an epidemic species that causes a typical hospital infection, the source of which is patients with CF, is more common in Russian patients. No effective schemes for the eradication and treatment of Bcc have been developed. Targeted therapy with ivacaftor + thesacaftor + elecsacaftor and ivacaftor modulator reduce the degree of Bcc contamination in sputum, but do not lead to its eradication. Lung transplantation in patients with Bcc proceeds with a large number of complications and may require long-term rehabilitation in the post-transplant period. Infection with hospital-acquired species of Bcc is associated with a more severe course of the disease and low survival, and infection with less epidemic species of Bcc probably determines the best prognosis for patients with CF. The role of infection of patients with “wild” species of Bcc has not been determined and requires further study.

   Conclusion. Prevention of cross-infection in patients with Всс remains a pressing issue.

   Increasing life expectancy of patients with cystic fibrosis is associated with an increased risk of systemic amyloidosis. At the same time, the rarity of this pathology determines the value of detailed analysis of individual clinical cases.

   The aim of the work was to discuss the pathogenesis and approaches to diagnosis, treatment, and prevention of complications of secondary amyloidosis in cystic fibrosis illustrated by a clinical case.

   Result. Mutation of the cystic fibrosis transmembrane regulatory protein gene leads to impaired function of the chlorine channel, which is localized mainly in the epithelial cells of the respiratory tract, salivary glands, sweat glands, pancreas, and intestine. As a result, mucociliary clearance of the respiratory tract becomes insufficient, which creates favorable conditions for the emergence and progression of respiratory infection and maintenance of chronic inflammation. The risk of secondary AA-amyloidosis in cystic fibrosis is associated with chronic inflammation and correlates with the level of markers of the acute phase of inflammation (C-reactive protein (CRP), serum amyloid A (SAA)). The article describes a 23-year-old patient. The manifestations of cystic fibrosis (recurrent respiratory infections and pancreatic insufficiency) were detected at birth. The diagnosis was made at the age of 2 years based on a sweat test; genotyping revealed a 2184insA/CFTRdele2,3 mutation. The peculiarity of the presented case is the development of secondary systemic amyloidosis in an adult patient with cystic fibrosis with kidney, liver, spleen, colon, and lymph node involvement. The clinical picture was dominated by nephrotic syndrome, which is associated with hypercoagulability due to loss of natural anticoagulant factors (antithrombin and protein S) with urine, as well as increased synthesis of procoagulants (factors V, VII, and fibrinogen). The immediate cause of death was pulmonary embolism from thrombosed veins of the lower legs, which is most likely associated with hypercoagulability and endothelial dysfunction due to nephrotic syndrome and secondary amyloidosis.

   Conclusion. Chronic systemic inflammation in cystic fibrosis contributes to the development of secondary amyloidosis with renal damage and the development of nephrotic syndrome, which in turn provokes hypercoagulability and the risk of thromboembolic complications.

   The increased risk of adverse drug reactions in patients with genetically determined features of drug metabolism is actively studied.

   The aim was to demonstrate the importance of taking into account pharmacogenetic features and drug interactions for the treatment of cystic fibrosis.

   Results. The article describes a case of toxic hepatitis in an 11-year-old child with cystic fibrosis (genotype F508del/F508del in the CFTR gene) and Gilbert’s syndrome (genotype 7TA/7TA in the UGT1A1 gene), who received targeted therapy with the drug elexacaftor/tezacaftor/ivacaftor + ivacaftor. The adverse reaction was provoked by interactions with other drugs, moderate CYP3A inhibitors (fluconazole and pyrantel) that were self-prescribed without consulting the doctor.

   Conclusion. When prescribing other drugs against the CFTR modulator treatment, it is necessary to take into account the interactions between the drugs according to the drug labels and it is advisable to determine the presence of Gilbert’s syndrome because of the lifelong use of targeted therapy.

   Diagnosis of many inherited diseases, particularly primary ciliary dyskinesia and cystic fibrosis (CF), remains inadequate. These diseases are often detected late in the course of infertility evaluation.

   The aim is to describe two clinical observations of male infertility with late detection of hereditary respiratory tract diseases.

   Methods. Two male patients, aged 33 and 32 years, with primary marital infertility due to total or subtotal asthenoteratozoospermia were studied. A comprehensive clinical examination, CT of the chest and paranasal sinuses, standard spermatological examination, electron microscopic examination of spermatozoa and nasal epithelial cells, CFTR gene sequencing, whole exome sequencing, and direct automated Sanger sequencing were performed.

   Results. Based on the results of a comprehensive genetic, pulmonological, andrological, and electron microscopic examination, both patients were diagnosed with autosomal recessive monogenic diseases associated with respiratory damage and primary male infertility. The patient with total asthenoteratozoospermia was diagnosed with primary ciliary dyskinesia (PCD) associated with probable pathogenic variants in the DRC1 gene, while the patient with obstructive azoospermia was diagnosed with a pancreatic-insufficient of cystic fibrosis caused by two pathogenic variants in the CFTR gene.

   Conclusion. The presented clinical cases demonstrate a prolonged diagnostic search in patients associated with an unpronounced clinical picture, lack of detailed anamnesis and appropriate investigations.

   The aim of this prospective comparative study was to search for variants of ACE, PPARGC1A, ACTN3, PPARA genes associated with nutritional status and body composition of children with cystic fibrosis (CF).

   Methods. Patients with CF (F508del/F508del) (n = 425) of 0 to 18 years old (the average age was 11.8 ± 3.8 years) were included in the study to assess their BMI, polymorphic gene variants, and body composition (for children over 5 years old) before and after 1 year of targeted therapy. The percentage (%) of active cellular body mass (ACM), skeletal muscle mass (SMM) and fat mass (FM) were assessed by Z-score. Single nucleotide polymorphisms (SNPs) of the ACE gene (rs1799752), the PPARGC1A gene (rs8192678), the ACTN3 gene (rs1815739), and the PPARA gene (rs4253778) were tested by PCR and RFLP analysis.

   Results. After a 1 year of targeted therapy, the body weight in boys significant raised by 5.3 (±2.5) kg, height by 5.7 (±1.7) cm (p < 0.01) and the body weight in girls increased by 4.5 (±1.9) kg, height by 4.8 (±1.3) cm (p < 0.01). The boys showed an raise in FM (%) from –0.23 to 0.13 SD (p = 0.04). In girls, the FM (%) increased from –0.15 to 0.08 SD (p = 0.02) and the % SMM lowered from 0.79 to 0.6 SD (p = 0.04). The RR genotype of the ACTN3 gene was associated with BMI deficiency (p = 0.048). Patients with the GA genotype of the PPARGC1A gene tended to have decreased ACM (%) (–1.1 – 2 SD) (p = 0.071) and very low ACM (%) (< –2.1 SD) (p = 0.062).

   Conclusion. An analysis of body composition in children with CF showed an increase in the proportion of fat mass after 1 year of targeted therapy. The RR genotype of the ACTN3 gene was associated with BMI deficiency.

   Elexacaftor/tezacaftor/ivacaftor + ivacaftor, a drug modulating the cystic fibrosis transmembrane conductance regulator protein, is currently revolutionizing the management of patients with cystic fibrosis, particularly those with at least one F508del variant. CFTR modulators are characterized by individual pharmacokinetic variability and a tendency to drug-drug interactions, which accounts for their variable effects in different patients. This article reports the experience of using the targeted therapy of cystic fibrosis, elexacaftor/tezacaftor/ivacaftor + ivacaftor, for the treatment of adult patients with cystic fibrosis for a year.

   The aim was to study the efficacy and side effects of the drug elexacaftor/tezacaftor/ivacaftor + ivacaftor during 12 months of treatment of adult patients with cystic fibrosis in the Omsk region.

   Methods. The article presents the experience of using elexacaftor/tezacaftor/ivacaftor + ivacaftor for targeted therapy of adult patients with CF for 12 months.

   Results. The positive effect, good tolerability and safety of the combined drug elexacaftor/tezacaftor/ivacaftor + ivacaftor for the treatment of adult patients with CF were demonstrated.

   Conclusion. Timely initiation of targeted therapy for CF in childhood is likely to prevent the development of severe manifestations of the disease, but monitoring of patients with CF receiving targeted therapy should be continued.