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4 results on '"Marina Starinova"'

1. Study of the genetic and molecular epidemiology of cystic fibrosis based on the patient registry for planning targeted therapy in Russian Federation

Author

Elena Kondratyeva, Yuliya Melyanovskaya, Victoriya Sherman, Anna Voronkova, Elena Zhekaite, Stanislav Krasovsky, Elena Amelina, Nataliya Kashirskaya, Vera Shadrina, Alexander Polyakov, Tagui Adyan, Olga Sсhagina, Marina Starinova, Elena Enina, Andrey Vasilyev, Andrey Marakhonov, Rena Zinchenko, and Sergey Kutsev

Subjects
cystic fibrosis, genetic epidemiology, CFTR gene variants, targeted therapy, disease prevalence, Genetics, QH426-470
Abstract

Cystic fibrosis (CF) is a genetically inherited disorder characterized by a wide range of clinical manifestations and genetic variations. This study focuses on the genetic and molecular epidemiology of CF in the Russian population, utilizing data from the national CF registry. The birth prevalence of CF in Russia has been analyzed over a span of years, revealing variations in frequency. The study delves into the genetic landscape of CFTR gene variants in Russian patients, showcasing a diverse spectrum with a predominance of severe variants, some of which are rare and distinct from global populations. A total of 233 variants have been documented, exhibiting frequencies ranging from 0.01% to 51.5%, with 47 of these variants remaining uncharted within international genetic databases. As of 2021, CFTR modulator therapy has been introduced for patients under 19 years, heightening the importance of genetic diagnosis. In 2023, more than 1,850 patients under 19 received CFTR modulator therapy. Notably, the impact of complex alleles on disease progression and response to targeted therapies is gaining recognition. Comparisons with European registries highlight distinctive features of the Russian population, such as differences in age distribution among patients. Additionally, the study emphasizes the need to ascertain clinical significance and pathogenicity of newly identified genetic variants, along with exploring their suitability for targeted therapies. The integration of genetic insights into the management of CF offers potential for enhanced personalized therapeutic interventions. In conclusion, this thorough analysis provides a comprehensive understanding of the genetic nuances within the Russian CF population. By illuminating the intricate relationship between genetic variations and disease manifestation, the study underscores the essential role of genetics in shaping therapeutic strategies and improving patient outcomes. Further research and ongoing genetic exploration are crucial for optimizing the care of individuals with CF in the era of evolving therapeutic options.

Published
2024
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2. Evaluation of the Complex p.[Leu467Phe;Phe508del] CFTR Allele in the Intestinal Organoids Model: Implications for Therapy

Author

Elena Kondratyeva, Anna Efremova, Yuliya Melyanovskaya, Anna Voronkova, Alexander Polyakov, Nataliya Bulatenko, Tagui Adyan, Viktoriya Sherman, Valeriia Kovalskaia, Nika Petrova, Marina Starinova, Tatiana Bukharova, Sergei Kutsev, and Dmitry Goldshtein

Subjects
Cystic Fibrosis, Colforsin, Organic Chemistry, Cystic Fibrosis Transmembrane Conductance Regulator, General Medicine, Catalysis, Computer Science Applications, Ligases, Organoids, Inorganic Chemistry, cystic fibrosis (CF), CFTR, complex allele [L467F, F508del], intestinal current measurements (ICM), intestinal organoids, CFTR modulators, Mutation, Humans, Benzodioxoles, Physical and Theoretical Chemistry, Molecular Biology, Alleles, Spectroscopy
Abstract

In the cohort of Russian patients with cystic fibrosis, the p.[Leu467Phe;Phe508del] complex allele (legacy name [L467F;F508del]) of the CFTR gene is understudied. In this research, we present the results of frequency evaluation of the [L467F;F508del] complex allele in the Russian Federation among patients with a F508del/F508del genotype, its effect on the clinical course of cystic fibrosis, the intestinal epithelium ionic channel function, and the effectiveness of target therapy. The frequency of the [L467F;F508del] complex allele among patients with homozygous F508del was determined with multiplex ligase-dependent probe amplification followed by polymerase chain reaction and fragment analysis. The function of ionic channels, including the residual CFTR function, and the effectiveness of CFTR modulators was analyzed using intestinal current measurements on rectal biopsy samples and the forskolin-induced swelling assay on organoids. The results showed that the F508del/[L467F;F508del] genotype is present in 8.2% of all Russian patients with F508del in a homozygous state. The clinical course of the disease in patients with the F508del/[L467F;F508del] genotype is severe and does not vary from the course in the cohort with homozygous F508del, although the CFTR channel function is significantly lower. For patients with the F508del/[L467F;F508del] genotype, we can recommend targeted therapy using a combined ivacaftor + tezacaftor + elexacaftor medication.

Published
2022
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3. Clinical and Functional Characteristics of the E92K CFTR Gene Variant in the Russian and Turkish Population of People with Cystic Fibrosis

Author

Elena Kondratyeva, Yuliya Melyanovskaya, Nataliya Bulatenko, Ksenia Davydenko, Alexandra Filatova, Anna Efremova, Mikhail Skoblov, Tatiana Bukharova, Viktoriya Sherman, Anna Voronkova, Elena Zhekaite, Stanislav Krasovskiy, Elena Amelina, Nika Petrova, Alexander Polyakov, Tagui Adyan, Marina Starinova, Maria Krasnova, Andrey Vasilyev, Oleg Makhnach, Rena Zinchenko, Sergey Kutsev, Yasemin Gokdemir, Bülent Karadag, Dmitry Goldshtein, and Kondratyeva E., Melyanovskaya Y., Bulatenko N., Davydenko K., Filatova A., Efremova A., Skoblov M., Bukharova T., Sherman V., Voronkova A., et al.

Subjects
Temel Bilimler (SCI), Mühendislik, ENGINEERING, Biochemistry, Physical Chemistry, Organik Kimya, Kimya, KİMYA, İNORGANİK VE NÜKLEER, CHEMISTRY, Biyokimya, Kimya Mühendisliği ve Teknolojisi, MÜHENDİSLİK, KİMYASAL, CHEMISTRY, INORGANIC & NUCLEAR, CFTR, intestinal current measurements (ICM), Spectroscopy, Bilgisayar Bilimi Uygulamaları, Computer Sciences, Moleküler Biyoloji, Temel Bilimler, Spektroskopi, KİMYA, FİZİKSEL, Fizikokimya, Life Sciences, CHEMISTRY, ORGANIC, Kataliz, genotype–phenotype correlation, General Medicine, Computer Science Applications, MOLECULAR BIOLOGY & GENETICS, Natural Sciences (SCI), Physical Sciences, Engineering and Technology, Bilgisayar Bilimi, Natural Sciences, cystic fibrosis (CF), İnorganik kimya, CHEMISTRY, PHYSICAL, E92K, Life Sciences (LIFE), Fiziksel ve Teorik Kimya, Molecular Biology and Genetics, Chemical Engineering and Technology, Catalysis, Inorganic Chemistry, SPEKTROSKOPİ, VX-809 corrector, KİMYA, ORGANİK, Yaşam Bilimleri, Bilgisayar Bilimleri, Biyoinorganik Kimya, Physical and Theoretical Chemistry, Engineering, Computing & Technology (ENG), Bioinorganic Chemistry, Molecular Biology, Moleküler Biyoloji ve Genetik, VX-770 potentiator, Organic Chemistry, Mühendislik, Bilişim ve Teknoloji (ENG), COMPUTER SCIENCE, Fizik Bilimleri, Yaşam Bilimleri (LIFE), intestinal organoids, CF Registry, forskolin-induced swelling (FIS) assay, Mühendislik ve Teknoloji, ENGINEERING, CHEMICAL
Abstract

The pathogenic variant E92K (c.274G > A) of the CFTR gene is rare in America and Europe, but it is common for people with cystic fibrosis from Russia and Turkey. We studied the effect of the E92K genetic variant on the CFTR function. The function of the CFTR channel was studied using the intestinal current measurements (ICM) method. The effects of CFTR modulators on the restoration of the CFTR function were studied in the model of intestinal organoids. To assess the effect of E92K on pre-mRNA splicing, the RT-PCR products obtained from patients’ intestinal organoid cultures were analyzed. Patients with the genetic variant E92K are characterized by an older age of diagnosis compared to homozygotes F508del and a high frequency of pancreatic sufficiency. The results of the sweat test and the ICM method showed partial preservation of the function of the CFTR channel. Functional analysis of CFTR gene expression revealed a weak effect of the E92K variant on mRNA-CFTR splicing. Lumacaftor (VX-809) has been shown to restore CFTR function in an intestinal organoid model, which allows us to consider the E92K variant as a promising target for therapy with CFTR correctors.

Published
2023
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