biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2026-26-2-127-143biopreparat-779Research ArticleТЕМА НОМЕРА: РАЗРАБОТКА ПРЕПАРАТОВ ДЛЯ ЛЕЧЕНИЯ РЕДКИХ (ОРФАННЫХ) ЗАБОЛЕВАНИЙISSUE TOPIC: DEVELOPMENT OF MEDICINAL PRODUCTS FOR THE TREATMENT OF RARE (ORPHAN) DISEASESЭволюция терапии моногенных орфанных заболеваний и регуляторные аспекты разработки орфанных препаратовEvolution of therapy monogenic orphan diseases and regulatory aspects of orphan medicinal products developmenthttps://orcid.org/0000-0003-2695-8869ПотеряевД. А.PoteryaevD. A.

Потеряев Дмитрий Александрович, канд. биол. наук

Ул. Владимирская, д. 14, пос. Вольгинский, городской округ Покров, Владимирская обл., 601125

Dmitry A. Poteryaev, Cand. Sci. (Biol.)

14 Vladimirskaya St., Volginsky, Pokrov municipal district, Vladimir region 601125

poteryaev@generium.ruhttps://orcid.org/0000-0002-1314-894XХамитовР. А.KhamitovR. A.

Хамитов Равиль Авгатович, д-р мед. наук, проф.

Ул. Владимирская, д. 14, пос. Вольгинский, городской округ Покров, Владимирская обл., 601125

Ravil A. Khamitov, Dr. Sci. (Med.), Prof.

14 Vladimirskaya St., Volginsky, Pokrov municipal district, Vladimir region 601125

Акционерное общество «ГЕНЕРИУМ»РоссияGENERIUM JSCRussian Federation202604072026262127143Copyright © Потеряев Д.А., Хамитов Р.А., 20262026Потеряев Д.А., Хамитов Р.А.Poteryaev D.A., Khamitov R.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/779ВВЕДЕНИЕ

ВВЕДЕНИЕ. В мире насчитывается от 6000 до 8000 описанных редких (орфанных) заболеваний (ОЗ), из которых около 80% имеют генетическую природу и часто являются жизнеугрожающими. Исторически разработка лекарственных средств (ЛС) для лечения ОЗ была затруднена из-за отсутствия экономических стимулов. За последние 10 лет в России наблюдается активный рост числа одобренных новых ЛС для ОЗ.

ЦЕЛЬ

ЦЕЛЬ. Проследить историю подходов к лечению наиболее распространенных моногенных орфанных заболеваний и провести анализ проблемных аспектов разработки орфанных препаратов и внедрения их в медицинскую практику.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Исторические примеры ОЗ иллюстрируют как медленный прогресс терапии от симптоматической до патогенетической (муковисцидоз), так и взрывной рост патогенетических ЛС разных типов действующих субстанций и механизмов действия там, где до этого не было никакой эффективной терапии (спинальная мышечная атрофия). Показан путь от симптоматического лечения и первых заместительных подходов до современных патогенетических и этиотропных стратегий лечения ОЗ, включая рекомбинантные белки, малые молекулы (потенциаторы и корректоры), олигонуклеотидные препараты, ферментозаместительную терапию и генную терапию на основе аденоассоциированных вирусных векторов. Особое внимание уделено подходам по преодолению таких барьеров, как вирусная безопасность, доставка препаратов через гематоэнцефалический барьер («троянские кони»), и проблемам коммерциализации генной терапии. Рассмотрены современные регуляторные механизмы и меры поддержки разработки орфанных ЛС в России, странах ЕАЭС и мире. Предлагаются пути гармонизации регуляторных требований для повышения доступности терапии.

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. Опыт последних десятилетий свидетельствует о трансформации подхода к ОЗ, которые перестали быть «безнадежными» и перешли в область наиболее интенсивного развития биомедицинских технологий. Дальнейший прогресс будет связан не только с созданием новых методов генной и клеточной терапии, но и с выстраиванием эффективных регуляторных, экономических и социальных механизмов, которые обеспечат равный доступ пациентов к терапии.

INTRODUCTION

INTRODUCTION. There are between 6,000 and 8,000 described rare (orphan) diseases worldwide, about 80% of which are genetic in origin and often life-threatening. Historically, the development of medicinal products (MPs) for RDs was hampered by a lack of economic incentives. Over the past 10 years, Russia has seen an active increase in the number of approved new MPs for RDs.

AIM

AIM. To trace the history of approaches to the treatment of the most common monogenic orphan diseases and analyze the problematic aspects of the development and implementation of orphan drugs in medical practice.

DISCUSSION

DISCUSSION. Historical examples of rare diseases illustrate both the slow progress of therapy from symptomatic to pathogenetic (cystic fibrosis) and the explosive growth of pathogenetic MPs of various modalities where no effective therapy existed before (spinal muscular atrophy). The path from symptomatic treatment and early replacement approaches to modern pathogenetic and etiotropic strategies is shown, including recombinant proteins, small molecules (potentiators and correctors), oligonucleotide-based drugs, enzyme replacement therapy, and gene therapy based on adeno-associated viral vectors. Special attention is paid to overcoming barriers such as viral safety, drug delivery across the blood-brain barrier ("Trojan horses"), and the challenges of commercializing gene therapy. The review examines current regulatory mechanisms and support measures for the development of orphan MPs in Russia, the EAEU countries, and the world.

CONCLUSIONS

CONCLUSIONS. The experience of recent decades indicates a transformation in the approach to rare diseases which have ceased to be "hopeless" and have become an area of the most intensive development in biomedical technologies. Further progress will be linked not only to the creation of new gene and cell therapy methods but also to the establishment of effective regulatory, economic, and social mechanisms ensuring equal patient access to therapy.

моногенные заболеванияредкие заболеванияорфанные заболеваниянаследственные заболеванияферментозаместительная терапиягенная терапияаденоассоциированные вирусные векторыгемофилиялизосомальные болезни накопленияспинальная мышечная атрофиярегуляторные аспектыклинические исследованияmonogenic diseasesrare diseasesorphan diseasescongenital diseasesenzyme replacement therapygene therapyadeno-associated virus vectorshemophilialysosomal storage diseasesspinal muscular atrophyregulatory aspectsclinical studiesРабота выполнена без спонсорской поддержки.The study was performed without external funding.ReferencesFranchini M, Mannucci PM. The more recent history of hemophilia treatment. Semin Thromb and Hemost. 2022; 48(8):904–10. https://doi.org/10.1055/s-0042-1756188Franchini M, Mannucci PM. The more recent history of hemophilia treatment. Semin Thromb and Hemost. 2022; 48(8):904–10. https://doi.org/10.1055/s-0042-1756188Румянцев АГ, Румянцев СА, Чернов ВМ. Гемофилия в практике врачей различных специальностей. М.: ГЭОТАР-Медиа; 2013. EDN: VHJICHRumyantsev AG, Rumyantsev SA, Chernov VM. Hemophilia in the practice of physicians of various specialties. Moscow: GEOTAR-Media; 2013 (In Russ.). EDN: VHJICHCatelli DH, Portich JP, Calvache ET, et al. Hemophilia: a biography on therapeutical approaches. Clin Biomed Res. 2023; 43(1):69–74. https://doi.org/10.22491/2357-9730.126437Catelli DH, Portich JP, Calvache ET, et al. Hemophilia: a biography on therapeutical approaches. Clin Biomed Res. 2023; 43(1):69–74. https://doi.org/10.22491/2357-9730.126437Hemophilia A and B: Global drug forecast and market analysis to 2030. London: Global Data; 2021.Hemophilia A and B: Global drug forecast and market analysis to 2030. London: Global Data; 2021.Егорова ТВ, Пискунов АА, Потеряев ДА. Генная терапия наследственных заболеваний на основе аденоассоциированных вирусных векторов: современные проблемы применения и пути их решения. БИОпрепараты. Профилактика, диагностика, лечение. 2024;24(2):123–39. https://doi.org/10.30895/2221-996X-2024-24-2-123-139Egorova TV, Piskunov AA, Poteryaev DA. Adeno-associated virus vector-based gene therapy for hereditary diseases: current problems of application and approaches to solve them. Biological Products. Prevention, Diagnosis, Treatment. 2024;24(2):123–39 (In Russ.). https://doi.org/10.30895/2221-996X-2024-24-2-123-139Navarro S. Historical compilation of cystic fibrosis. Gastroenterol Hepatol. 2016;39(1):36–42 (In Spanish). https://doi.org/10.1016/j.gastrohep.2015.04.012Navarro S. Historical compilation of cystic fibrosis. Gastroenterol Hepatol. 2016;39(1):36–42 (In Spanish). https://doi.org/10.1016/j.gastrohep.2015.04.012Shire SJ. Stability characterization and formulation development of recombinant human deoxyribonuclease I [Pulmozyme®, (Dornase Alpha)]. In: Formulation, characterization, and stability of protein drugs: case histories. Boston: Springer; 2002. P. 393–426. https://doi.org/10.1007/0-306-47452-2_11Shire SJ. Stability characterization and formulation development of recombinant human deoxyribonuclease I [Pulmozyme®, (Dornase Alpha)]. In: Formulation, characterization, and stability of protein drugs: case histories. Boston: Springer; 2002. P. 393–426. https://doi.org/10.1007/0-306-47452-2_11Cystic fibrosis patients in Canada live nearly a decade longer than those in US, study finds. BMJ. 2017;356:j1346. https://doi.org/10.1136/bmj.j1346Cystic fibrosis patients in Canada live nearly a decade longer than those in US, study finds. BMJ. 2017;356:j1346. https://doi.org/10.1136/bmj.j1346Сафронова НС, Машковская ДВ, Козелько ЕВ. Пути повышения эффективности кинезитерапии у детей с муковисцидозом. Современные вопросы биомедицины. 2022;6(1):50. https://doi.org/10.51871/2588-0500_2022_06_01_50Safronova NS, Mashkovskaya DV, Kozel’ko EV. Ways to increase the effectiveness of kinesitherapy in children with cystic fibrosis. Modern Issues of Biomedicine. 2022;6(1):50 (In Russ.). https://doi.org/10.51871/2588-0500_2022_06_01_50Chaudary N. Triplet CFTR modulators: Future prospects for treatment of cystic fibrosis. Ther Clin Risk Manag. 2018;14:2375–83. https://doi.org/10.2147/TCRM.S147164Chaudary N. Triplet CFTR modulators: Future prospects for treatment of cystic fibrosis. Ther Clin Risk Manag. 2018;14:2375–83. https://doi.org/10.2147/TCRM.S147164Massie J, Robinson PJ, Cooper PJ. The story of cystic fibrosis 1965–2015. J Paediatr Child Health. 2016;52(11):991–4. https://doi.org/10.1111/jpc.13309Massie J, Robinson PJ, Cooper PJ. The story of cystic fibrosis 1965–2015. J Paediatr Child Health. 2016;52(11):991–4. https://doi.org/10.1111/jpc.13309Bell SC, Mall MA, Gutierrez H, et al. The future of cystic fibrosis care: A global perspective. Lancet Respir Med. 2020;8(1):65–124. https://doi.org/10.1016/S2213-2600(19)30337-6Bell SC, Mall MA, Gutierrez H, et al. The future of cystic fibrosis care: A global perspective. Lancet Respir Med. 2020;8(1):65–124. https://doi.org/10.1016/S2213-2600(19)30337-6Allen L, Allen L, Carr SB, et al. Future therapies for cystic fibrosis. Nat Commun. 2023;14(1):693. https://doi.org/10.1038/s41467-023-36244-2Allen L, Allen L, Carr SB, et al. Future therapies for cystic fibrosis. Nat Commun. 2023;14(1):693. https://doi.org/10.1038/s41467-023-36244-2Sui H, Xu X, Su Y, et al. Gene therapy for cystic fibrosis: Challenges and prospects. Front Pharmacol. 2022;13:1015926. https://doi.org/10.3389/fphar.2022.1015926Sui H, Xu X, Su Y, et al. Gene therapy for cystic fibrosis: Challenges and prospects. Front Pharmacol. 2022;13:1015926. https://doi.org/10.3389/fphar.2022.1015926Kireeva TN, Zhigalina DI, Skryabin NA. Cystic fibrosis therapy: From symptoms to the cause of the disease. Vavilov J Genet Breed. 2025;29(2):279–89. https://doi.org/10.18699/vjgb-25-31Kireeva TN, Zhigalina DI, Skryabin NA. Cystic fibrosis therapy: From symptoms to the cause of the disease. Vavilov J Genet Breed. 2025;29(2):279–89. https://doi.org/10.18699/vjgb-25-31Liu X, Campos-Gomez J, Luo M, et al. LUNAR LNP delivery of CFTR mRNA restores channel function and improves mucociliary clearance in ferret cystic fibrosis airways. Mol Ther. 2026;34(4):2044–62. https://doi.org/10.1016/j.ymthe.2025.12.040Liu X, Campos-Gomez J, Luo M, et al. LUNAR LNP delivery of CFTR mRNA restores channel function and improves mucociliary clearance in ferret cystic fibrosis airways. Mol Ther. 2026;34(4):2044–62. https://doi.org/10.1016/j.ymthe.2025.12.040Carrozzo I, Maule G, Gentile C, et al. Functional rescue of F508del-CFTR through revertant mutations introduced by CRISPR base editing. Mol Ther. 2025;33(3):970–85. https://doi.org/10.1016/j.ymthe.2025.01.011Carrozzo I, Maule G, Gentile C, et al. Functional rescue of F508del-CFTR through revertant mutations introduced by CRISPR base editing. Mol Ther. 2025;33(3):970–85. https://doi.org/10.1016/j.ymthe.2025.01.011Nishio H, Niba ETE, Saito T, et al. Spinal muscular atrophy: The past, present, and future of diagnosis and treatment. Int J Mol Sci. 2023;24(15):11939. https://doi.org/10.3390/ijms241511939Nishio H, Niba ETE, Saito T, et al. Spinal muscular atrophy: The past, present, and future of diagnosis and treatment. Int J Mol Sci. 2023;24(15):11939. https://doi.org/10.3390/ijms241511939Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–65. https://doi.org/10.1016/0092-8674(95)90460-3Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–65. https://doi.org/10.1016/0092-8674(95)90460-3Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723–32. https://doi.org/10.1056/NEJMoa1702752Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723–32. https://doi.org/10.1056/NEJMoa1702752Hoy SM. Onasemnogene abeparvovec: First global approval. Drugs. 2019;79(11):1255–62. https://doi.org/10.1007/s40265-019-01162-5Hoy SM. Onasemnogene abeparvovec: First global approval. Drugs. 2019;79(11):1255–62. https://doi.org/10.1007/s40265-019-01162-5Kokaliaris C, Evans R, Hawkins N, et al. Long-term comparative efficacy and safety of risdiplam and nusinersen in children with type 1 spinal muscular atrophy. Adv Ther. 2024;41(6):2414–34. https://doi.org/10.1007/s12325-024-02845-6Kokaliaris C, Evans R, Hawkins N, et al. Long-term comparative efficacy and safety of risdiplam and nusinersen in children with type 1 spinal muscular atrophy. Adv Ther. 2024;41(6):2414–34. https://doi.org/10.1007/s12325-024-02845-6Futerman AH, van Meer G. The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol. 2004;5(7):554–65. https://doi.org/10.1038/nrm1423Futerman AH, van Meer G. The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol. 2004;5(7):554–65. https://doi.org/10.1038/nrm1423de Duve C. From cytases to lysosomes. Fed Proc. 1964;23:1045–9. PMID: 14209796de Duve C. From cytases to lysosomes. Fed Proc. 1964;23:1045–9. PMID: 14209796Solomon M, Muro S. Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives. Adv Drug Deliv Rev. 2017;118:109–34. https://doi.org/10.1016/j.addr.2017.05.004Solomon M, Muro S. Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives. Adv Drug Deliv Rev. 2017;118:109–34. https://doi.org/10.1016/j.addr.2017.05.004Ago Y, Rintz E, Musini KS, et al. Molecular mechanisms in pathophysiology of mucopolysaccharidosis and prospects for innovative therapy. Int J Mol Sci. 2024;25(2):1113. https://doi.org/10.3390/ijms25021113Ago Y, Rintz E, Musini KS, et al. Molecular mechanisms in pathophysiology of mucopolysaccharidosis and prospects for innovative therapy. Int J Mol Sci. 2024;25(2):1113. https://doi.org/10.3390/ijms25021113Kobayashi H. Gene therapy for lysosomal storage diseases. Brain Dev. 2025;47(5):104399. https://doi.org/10.1016/j.braindev.2025.104399Kobayashi H. Gene therapy for lysosomal storage diseases. Brain Dev. 2025;47(5):104399. https://doi.org/10.1016/j.braindev.2025.104399Suzuki Y. Chemical chaperone therapy for GM1-gangliosidosis. Cell Mol Life Sci. 2008;65(3):351–3. https://doi.org/10.1007/s00018-008-7470-2Suzuki Y. Chemical chaperone therapy for GM1-gangliosidosis. Cell Mol Life Sci. 2008;65(3):351–3. https://doi.org/10.1007/s00018-008-7470-2Platt FM, Jeyakumar M. Substrate reduction therapy. Acta Paediatr. 2008;97(457):88–93. https://doi.org/10.1111/j.1651-2227.2008.00656.xPlatt FM, Jeyakumar M. Substrate reduction therapy. Acta Paediatr. 2008;97(457):88–93. https://doi.org/10.1111/j.1651-2227.2008.00656.xBiffi A. Hematopoietic stem cell gene therapy for storage disease: Current and new indications. Mol Ther. 2017;25(5):1155–62. https://doi.org/10.1016/j.ymthe.2017.03.025Biffi A. Hematopoietic stem cell gene therapy for storage disease: Current and new indications. Mol Ther. 2017;25(5):1155–62. https://doi.org/10.1016/j.ymthe.2017.03.025Narita K, Choudhury A, Dobrenis K, et al. Protein transduction of Rab9 in Niemann-Pick C cells reduces cholesterol storage. FASEB J. 2005;19(11):1558–60. https://doi.org/10.1096/fj.04-2714fjeNarita K, Choudhury A, Dobrenis K, et al. Protein transduction of Rab9 in Niemann-Pick C cells reduces cholesterol storage. FASEB J. 2005;19(11):1558–60. https://doi.org/10.1096/fj.04-2714fjeFolts CJ, Scott-Hewitt N, Pröschel C, et al. Lysosomal re-acidification prevents lysosphingolipid-induced lysosomal impairment and cellular toxicity. PLoS Biol. 2016;14(12):e1002583. https://doi.org/10.1371/journal.pbio.1002583Folts CJ, Scott-Hewitt N, Pröschel C, et al. Lysosomal re-acidification prevents lysosphingolipid-induced lysosomal impairment and cellular toxicity. PLoS Biol. 2016;14(12):e1002583. https://doi.org/10.1371/journal.pbio.1002583Medina DL, Fraldi A, Bouche V, et al. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell. 2011;21(3):421–30. https://doi.org/10.1016/j.devcel.2011.07.016Medina DL, Fraldi A, Bouche V, et al. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell. 2011;21(3):421–30. https://doi.org/10.1016/j.devcel.2011.07.016Nishijima K, Okuzaki Y. Pharmaceutical protein production by transgenic chickens: Several viewpoints towards the next stage. Protein Expr Purif. 2026;240:106900. https://doi.org/10.1016/j.pep.2026.106900Nishijima K, Okuzaki Y. Pharmaceutical protein production by transgenic chickens: Several viewpoints towards the next stage. Protein Expr Purif. 2026;240:106900. https://doi.org/10.1016/j.pep.2026.106900Leal AF, Inci OK, Seyrantepe V, et al. Molecular Trojan Horses for treating lysosomal storage diseases. Mol Genet Metab. 2023;140(3):107648. https://doi.org/10.1016/j.ymgme.2023.107648Leal AF, Inci OK, Seyrantepe V, et al. Molecular Trojan Horses for treating lysosomal storage diseases. Mol Genet Metab. 2023;140(3):107648. https://doi.org/10.1016/j.ymgme.2023.107648Научно-практическая конференция «Достижения и перспективы российских биотехнологий в лечении мукополисахаридоза II типа». Педиатрическая фармакология. 2025;22(6):768–72. https://doi.org/10.15690/pf.v22i6.2998Scientific and practical conference “Achievements and prospects of Russian biotechnologies in the treatment of type II mucopolysaccharidosis”. Pediatric Pharmacology. 2025;22(6):768–72 (In Russ.). https://doi.org/10.15690/pf.v22i6.2998Okuyama T, Eto Y, Sakai N, et al. A phase 2/3 trial of pabinafusp alfa, IDS fused with anti-human transferrin receptor antibody, targeting neurodegeneration in MPS-II. Molecular Therapy. 2021;29(2):671–9. https://doi.org/10.1016/j.ymthe.2020.09.039Okuyama T, Eto Y, Sakai N, et al. A phase 2/3 trial of pabinafusp alfa, IDS fused with anti-human transferrin receptor antibody, targeting neurodegeneration in MPS-II. Molecular Therapy. 2021;29(2):671–9. https://doi.org/10.1016/j.ymthe.2020.09.039Hamad AA, Alkhawaldeh IM, Nashwan AJ, et al. Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis. Neurol Sci. 2025;46(5):1977–85. https://doi.org/10.1007/s10072-025-07994-2Hamad AA, Alkhawaldeh IM, Nashwan AJ, et al. Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis. Neurol Sci. 2025;46(5):1977–85. https://doi.org/10.1007/s10072-025-07994-2Fernandez-Pombo A, Diaz-Lopez EJ, Castro AI, et al. Clinical spectrum of LMNA-associated type 2 familial partial lipodystrophy: A systematic review. Cells. 2023;12(5):725. https://doi.org/10.3390/cells12050725Fernandez-Pombo A, Diaz-Lopez EJ, Castro AI, et al. Clinical spectrum of LMNA-associated type 2 familial partial lipodystrophy: A systematic review. Cells. 2023;12(5):725. https://doi.org/10.3390/cells12050725Byun S, Lee M, Kim M. Gene therapy for Huntington’s disease: The final strategy for a cure? J Mov Disord. 2022;15(1):15–20. https://doi.org/10.14802/jmd.21006Byun S, Lee M, Kim M. Gene therapy for Huntington’s disease: The final strategy for a cure? J Mov Disord. 2022;15(1):15–20. https://doi.org/10.14802/jmd.21006Zheng Y, Li F, Shi J. Advances in STXBP1 encephalopathy research and translational opportunities. J Neurorestoratology. 2024;12(3):100134. https://doi.org/10.1016/j.jnrt.2024.100134Zheng Y, Li F, Shi J. Advances in STXBP1 encephalopathy research and translational opportunities. J Neurorestoratology. 2024;12(3):100134. https://doi.org/10.1016/j.jnrt.2024.100134Delvecchio M, Pastore C, Giordano P. Treatment options for MODY patients: A systematic review of literature. Diabetes Ther. 2020;11(8):1667–85. https://doi.org/10.1007/s13300-020-00864-4Delvecchio M, Pastore C, Giordano P. Treatment options for MODY patients: A systematic review of literature. Diabetes Ther. 2020;11(8):1667–85. https://doi.org/10.1007/s13300-020-00864-4Chehelgerdi M, Chehelgerdi M, Khorramian-Ghahfarokhi M, et al. Comprehensive review of CRISPR-based gene edi­ting: Mechanisms, challenges, and applications in cancer therapy. Mol Cancer. 2024;23(1):9. https://doi.org/10.1186/s12943-023-01925-5Chehelgerdi M, Chehelgerdi M, Khorramian-Ghahfarokhi M, et al. Comprehensive review of CRISPR-based gene edi­ting: Mechanisms, challenges, and applications in cancer therapy. Mol Cancer. 2024;23(1):9. https://doi.org/10.1186/s12943-023-01925-5Mücke MM, Fong S, Foster GR, et al. Adeno-associated viruses for gene therapy — clinical implications and liver-related complications, a guide for hepatologists. J Hepatol. 2024;80(2):352–61. https://doi.org/10.1016/j.jhep.2023.10.029Mücke MM, Fong S, Foster GR, et al. Adeno-associated viruses for gene therapy — clinical implications and liver-related complications, a guide for hepatologists. J Hepatol. 2024;80(2):352–61. https://doi.org/10.1016/j.jhep.2023.10.029

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