Редакторы оснований ДНК — перспективный инструмент для генной терапии вирусных инфекций человека

Авторы:

Алиев Т.И.,

Иматдинов И.Р.

Журнал: Молекулярная генетика, микробиология и вирусология. 2025;43(3):4-8.

DOI: 10.17116/molgen2025430314

Прочитано: 1134 раза

Резюме

Одним из громких достижений в области геномного редактирования стало применение редакторов оснований ДНК. Данный подход заключается в точечном редактировании азотистых оснований в ДНК живых клеток. Поскольку подобный способ редактирования не подразумевает внесение двуцепочечных разрывов, как например, широко распространенный метод CRISPR-Cas, то редакторы оснований являются многообещающим инструментом в генной терапии путем временного изменения оснований РНК или постоянного изменения оснований ДНК. Последние достижения в области специфичности, эффективности, точности и доставки редакторов оснований открывают новые терапевтические возможности для этих технологий. Можно предположить, что коррекция однонуклеотидных мутаций станет одним из направлений прецизионной медицины будущего.

Ключевые слова

обзор
редактор оснований цитозина
редактор оснований аденина
генная терапия
вирусные инфекции

Дата поступления: 03.03.2025

Дата принятия в печать: 26.05.2025

Дата публикации: 02.10.2025

Литература / References

Cradick TJ, Ambrosini G, Iseli C, Bucher P, McCaffrey AP. ZFN-Site searches genomes for zinc finger nuclease target sites and off-target sites. BMC Bioinformatics. 2011;12:152. https://doi.org/10.1186/1471-2105-12-152
Mushtaq M, Bhat JA, Mir ZA, Sakina A, Ali S, Singh AK, et al. CRISPR/Cas approach: A new way of looking at plant-abiotic interactions. J Plant Physiol. 2018;225:156-162. https://doi.org/10.1016/j.jplph.2018.04.001
Sakovina L, Vokhtantsev I, Vorobyeva M, Vorobyev P, Novopashina D. Improving Stability and Specificity of CRISPR/Cas9 System by Selective Modification of Guide RNAs with 2′-fluoro and Locked Nucleic Acid Nucleotides. Int. J. Mol. Sci. 2022;23(21):13460. https://doi.org/10.3390/ijms232113460
Jeong YK, Lee S, Hwang GH, Hong SA, Park SE, Kim JS, et al. Adenine base editor engineering reduces editing of bystander cytosines. Nat Biotechnol. 2021;39(11):1426-1433. https://doi.org/10.1038/s41587-021-00943-2
Brezgin S, Kostyusheva A, Kostyushev D, Chulanov V. Dead Cas Systems: Types, Principles, and Applications. Int J Mol Sci. 2019;20(23):6041. https://doi.org/10.3390/ijms20236041
Bigelyte G, Duchovska B, Zedaveinyte R, Sasnauskas G, Sinkunas T, Dalgediene I, et al. Innate programmable DNA binding by CRISPR-Cas12m effectors enable efficient base editing. Nucleic Acids Res. 2024;52(6):3234-3248. https://doi.org/10.1093/nar/gkae016
Wu WY, Mohanraju P, Liao C, Adiego-Pérez B, Creutzburg SCA, Makarova KS, et al. The miniature CRISPR-Cas12m effector binds DNA to block transcription. Mol Cell. 2022;82(23):4487-4502.e7. https://doi.org/10.1016/j.molcel.2022.11.003
Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533(7603):420-424. https://doi.org/10.1038/nature17946
Schormann N, Ricciardi R, Chattopadhyay D. Uracil-DNA glycosylases-structural and functional perspectives on an essential family of DNA repair enzymes. Protein Sci. 2014;23(12):1667-85. https://doi.org/10.1002/pro.2554
Carrington B, Weinstein RN, Sood R. BE4max and AncBE4max Are Efficient in Germline Conversion of C:G to T:A Base Pairs in Zebrafish. Cells. 2020;9(7):1690. https://doi.org/10.3390/cells9071690
Neugebauer ME, Hsu A, Arbab M, Krasnow NA, McElroy AN, Pandey S, et al. Evolution of an adenine base editor into a small, efficient cytosine base editor with low off-target activity. Nat Biotechnol. 2023;41(5):673-685. https://doi.org/10.1038/s41587-022-01533-6
Keegan LP, Hajji K, O’Connell MA. Adenosine Deaminase Acting on RNA (ADAR) Enzymes: A Journey from Weird to Wondrous. Acc Chem Res. 2023;56(22):3165-3174. https://doi.org/10.1021/acs.accounts.3c00433
Soma A, Kubota A, Tomoe D, Ikeuchi Y, Kawamura F, Arimoto H, et al. yaaJ, the tRNA-Specific Adenosine Deaminase, Is Dispensable in Bacillus subtilis. Genes (Basel). 2023;14(8):1515. https://doi.org/10.3390/genes14081515
Ranzau BL, Rallapalli KL, Evanoff M, Paesani F, Komor AC. The Wild-Type tRNA Adenosine Deaminase Enzyme TadA Is Capable of Sequence-Specific DNA Base Editing. Chembiochem. 2023;24(16):e202200788. https://doi.org/10.1002/cbic.202200788
Kim J, Malashkevich V, Roday S, Lisbin M, Schramm VL, Almo SC. Structural and kinetic characterization of Escherichia coli TadA, the wobble-specific tRNA deaminase. Biochemistry. 2006;45(20):6407-16. https://doi.org/10.1021/bi0522394
Shi K, Carpenter MA, Banerjee S, Shaban NM, Kurahashi K, Salamango DJ, et al. Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B. Nat Struct Mol Biol. 2017;24(2):131-139. https://doi.org/10.1038/nsmb.3344
Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature. 2017;551(7681):464-471. https://doi.org/10.1038/nature24644
Zhang X, Zhu B, Chen L, Xie L, Yu W, Wang Y, et al. Dual base editor catalyzes both cytosine and adenine base conversions in human cells. Nature Biotechnology. 2020;38(7):856-860. https://doi.org/10.1038/s41587-020-0527-y
Wang JH, Gessler DJ, Zhan W, Gallagher TL, Gao G. Adeno-associated virus as a delivery vector for gene therapy of human diseases. Sig Transduct Target Ther. 2024;9(1):78. https://doi.org/10.1038/s41392-024-01780-w
Poorolajal J, Hooshmand E, Mahjub H, Esmailnasab N, Jenabi E. Survival rate of AIDS disease and mortality in HIV-infected patients: a meta-analysis. Public Health. 2016;139:3-12. https://doi.org/10.1016/j.puhe.2016.05.004
Xiao T, Cai Y, Chen B. HIV-1 Entry and Membrane Fusion Inhibitors. Viruses. 2021;13(5):735. https://doi.org/10.3390/v13050735
DiGiusto DL, Cannon PM, Holmes MC, Li L, Rao A, Wang J, et al. Preclinical development and qualification of ZFN-mediated CCR5 disruption in human hematopoietic stem/progenitor cells. Mol Ther Methods Clin Dev. 2016;3:16067. https://doi.org/10.1038/mtm.2016.67
Khamaikawin W, Saisawang C, Tassaneetrithep B, Bhukhai K, Phanthong P, Borwornpinyo S, et al. CRISPR/Cas9 genome editing of CCR5 combined with C46 HIV-1 fusion inhibitor for cellular resistant to R5 and X4 tropic HIV-1. Sci Rep. 2024;14(1):10852. https://doi.org/10.1038/s41598-024-61626-x
Liu Y, Binda CS, Berkhout B, Das AT. CRISPR-Cas attack of HIV-1 proviral DNA can cause unintended deletion of surrounding cellular DNA. J Virol. 2023;97(12):e0133423. https://doi.org/10.1128/jvi.01334-23
Knipping F, Newby GA, Eide CR, McElroy AN, Nielsen SC, Smith K, et al. Disruption of HIV-1 co-receptors CCR5 and CXCR4 in primary human T cells and hematopoietic stem and progenitor cells using base editing. Mol Ther. 2022;30(1):130-144. https://doi.org/10.1016/j.ymthe.2021.10.026
Revill PA, Chisari FV, Block JM, Dandri M, Gehring AJ, Guo H, et al. A global scientific strategy to cure hepatitis B. Lancet Gastroenterol Hepatol. 2019;4(7):545-558. https://doi.org/10.1016/S2468-1253(19)30119-0
Wei L, Ploss A. Mechanism of Hepatitis B Virus cccDNA Formation. Viruses. 2021;13(8):1463. https://doi.org/10.3390/v13081463
Xia Y, Liang TJ. Development of Direct-acting Antiviral and Host-targeting Agents for Treatment of Hepatitis B Virus Infection. Gastroenterology. 2019;156(2):311-324. https://doi.org/10.1053/j.gastro.2018.07.057
Smekalova EM, Martinez MG, Combe E, Kumar A, Dejene S, Leboeuf D, et al. Cytosine base editing inhibits hepatitis B virus replication and reduces HBsAg expression in vitro and in vivo. Mol Ther Nucleic Acids. 2023;35(1):102112. https://doi.org/10.1016/j.omtn.2023.102112

Редакторы оснований ДНК — перспективный инструмент для генной терапии вирусных инфекций человека

Авторы:

Алиев Т.И.,

Иматдинов И.Р.

Журнал: Молекулярная генетика, микробиология и вирусология. 2025;43(3):4-8.

DOI: 10.17116/molgen2025430314

Прочитано: 1134 раза

Резюме

Ключевые слова

обзор
редактор оснований цитозина
редактор оснований аденина
генная терапия
вирусные инфекции

Дата поступления: 03.03.2025

Дата принятия в печать: 26.05.2025

Дата публикации: 02.10.2025

Литература / References

Cradick TJ, Ambrosini G, Iseli C, Bucher P, McCaffrey AP. ZFN-Site searches genomes for zinc finger nuclease target sites and off-target sites. BMC Bioinformatics. 2011;12:152. https://doi.org/10.1186/1471-2105-12-152
Mushtaq M, Bhat JA, Mir ZA, Sakina A, Ali S, Singh AK, et al. CRISPR/Cas approach: A new way of looking at plant-abiotic interactions. J Plant Physiol. 2018;225:156-162. https://doi.org/10.1016/j.jplph.2018.04.001
Sakovina L, Vokhtantsev I, Vorobyeva M, Vorobyev P, Novopashina D. Improving Stability and Specificity of CRISPR/Cas9 System by Selective Modification of Guide RNAs with 2′-fluoro and Locked Nucleic Acid Nucleotides. Int. J. Mol. Sci. 2022;23(21):13460. https://doi.org/10.3390/ijms232113460
Jeong YK, Lee S, Hwang GH, Hong SA, Park SE, Kim JS, et al. Adenine base editor engineering reduces editing of bystander cytosines. Nat Biotechnol. 2021;39(11):1426-1433. https://doi.org/10.1038/s41587-021-00943-2
Brezgin S, Kostyusheva A, Kostyushev D, Chulanov V. Dead Cas Systems: Types, Principles, and Applications. Int J Mol Sci. 2019;20(23):6041. https://doi.org/10.3390/ijms20236041
Bigelyte G, Duchovska B, Zedaveinyte R, Sasnauskas G, Sinkunas T, Dalgediene I, et al. Innate programmable DNA binding by CRISPR-Cas12m effectors enable efficient base editing. Nucleic Acids Res. 2024;52(6):3234-3248. https://doi.org/10.1093/nar/gkae016
Wu WY, Mohanraju P, Liao C, Adiego-Pérez B, Creutzburg SCA, Makarova KS, et al. The miniature CRISPR-Cas12m effector binds DNA to block transcription. Mol Cell. 2022;82(23):4487-4502.e7. https://doi.org/10.1016/j.molcel.2022.11.003
Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533(7603):420-424. https://doi.org/10.1038/nature17946
Schormann N, Ricciardi R, Chattopadhyay D. Uracil-DNA glycosylases-structural and functional perspectives on an essential family of DNA repair enzymes. Protein Sci. 2014;23(12):1667-85. https://doi.org/10.1002/pro.2554
Carrington B, Weinstein RN, Sood R. BE4max and AncBE4max Are Efficient in Germline Conversion of C:G to T:A Base Pairs in Zebrafish. Cells. 2020;9(7):1690. https://doi.org/10.3390/cells9071690
Neugebauer ME, Hsu A, Arbab M, Krasnow NA, McElroy AN, Pandey S, et al. Evolution of an adenine base editor into a small, efficient cytosine base editor with low off-target activity. Nat Biotechnol. 2023;41(5):673-685. https://doi.org/10.1038/s41587-022-01533-6
Keegan LP, Hajji K, O’Connell MA. Adenosine Deaminase Acting on RNA (ADAR) Enzymes: A Journey from Weird to Wondrous. Acc Chem Res. 2023;56(22):3165-3174. https://doi.org/10.1021/acs.accounts.3c00433
Soma A, Kubota A, Tomoe D, Ikeuchi Y, Kawamura F, Arimoto H, et al. yaaJ, the tRNA-Specific Adenosine Deaminase, Is Dispensable in Bacillus subtilis. Genes (Basel). 2023;14(8):1515. https://doi.org/10.3390/genes14081515
Ranzau BL, Rallapalli KL, Evanoff M, Paesani F, Komor AC. The Wild-Type tRNA Adenosine Deaminase Enzyme TadA Is Capable of Sequence-Specific DNA Base Editing. Chembiochem. 2023;24(16):e202200788. https://doi.org/10.1002/cbic.202200788
Kim J, Malashkevich V, Roday S, Lisbin M, Schramm VL, Almo SC. Structural and kinetic characterization of Escherichia coli TadA, the wobble-specific tRNA deaminase. Biochemistry. 2006;45(20):6407-16. https://doi.org/10.1021/bi0522394
Shi K, Carpenter MA, Banerjee S, Shaban NM, Kurahashi K, Salamango DJ, et al. Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B. Nat Struct Mol Biol. 2017;24(2):131-139. https://doi.org/10.1038/nsmb.3344
Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature. 2017;551(7681):464-471. https://doi.org/10.1038/nature24644
Zhang X, Zhu B, Chen L, Xie L, Yu W, Wang Y, et al. Dual base editor catalyzes both cytosine and adenine base conversions in human cells. Nature Biotechnology. 2020;38(7):856-860. https://doi.org/10.1038/s41587-020-0527-y
Wang JH, Gessler DJ, Zhan W, Gallagher TL, Gao G. Adeno-associated virus as a delivery vector for gene therapy of human diseases. Sig Transduct Target Ther. 2024;9(1):78. https://doi.org/10.1038/s41392-024-01780-w
Poorolajal J, Hooshmand E, Mahjub H, Esmailnasab N, Jenabi E. Survival rate of AIDS disease and mortality in HIV-infected patients: a meta-analysis. Public Health. 2016;139:3-12. https://doi.org/10.1016/j.puhe.2016.05.004
Xiao T, Cai Y, Chen B. HIV-1 Entry and Membrane Fusion Inhibitors. Viruses. 2021;13(5):735. https://doi.org/10.3390/v13050735
DiGiusto DL, Cannon PM, Holmes MC, Li L, Rao A, Wang J, et al. Preclinical development and qualification of ZFN-mediated CCR5 disruption in human hematopoietic stem/progenitor cells. Mol Ther Methods Clin Dev. 2016;3:16067. https://doi.org/10.1038/mtm.2016.67
Khamaikawin W, Saisawang C, Tassaneetrithep B, Bhukhai K, Phanthong P, Borwornpinyo S, et al. CRISPR/Cas9 genome editing of CCR5 combined with C46 HIV-1 fusion inhibitor for cellular resistant to R5 and X4 tropic HIV-1. Sci Rep. 2024;14(1):10852. https://doi.org/10.1038/s41598-024-61626-x
Liu Y, Binda CS, Berkhout B, Das AT. CRISPR-Cas attack of HIV-1 proviral DNA can cause unintended deletion of surrounding cellular DNA. J Virol. 2023;97(12):e0133423. https://doi.org/10.1128/jvi.01334-23
Knipping F, Newby GA, Eide CR, McElroy AN, Nielsen SC, Smith K, et al. Disruption of HIV-1 co-receptors CCR5 and CXCR4 in primary human T cells and hematopoietic stem and progenitor cells using base editing. Mol Ther. 2022;30(1):130-144. https://doi.org/10.1016/j.ymthe.2021.10.026
Revill PA, Chisari FV, Block JM, Dandri M, Gehring AJ, Guo H, et al. A global scientific strategy to cure hepatitis B. Lancet Gastroenterol Hepatol. 2019;4(7):545-558. https://doi.org/10.1016/S2468-1253(19)30119-0
Wei L, Ploss A. Mechanism of Hepatitis B Virus cccDNA Formation. Viruses. 2021;13(8):1463. https://doi.org/10.3390/v13081463
Xia Y, Liang TJ. Development of Direct-acting Antiviral and Host-targeting Agents for Treatment of Hepatitis B Virus Infection. Gastroenterology. 2019;156(2):311-324. https://doi.org/10.1053/j.gastro.2018.07.057
Smekalova EM, Martinez MG, Combe E, Kumar A, Dejene S, Leboeuf D, et al. Cytosine base editing inhibits hepatitis B virus replication and reduces HBsAg expression in vitro and in vivo. Mol Ther Nucleic Acids. 2023;35(1):102112. https://doi.org/10.1016/j.omtn.2023.102112

Редакторы оснований ДНК — перспективный инструмент для генной терапии вирусных инфекций человека

Резюме

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Редакторы оснований ДНК — перспективный инструмент для генной терапии вирусных инфекций человека

Резюме

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