Fundamentos da Terapia Gênica baseada em vetores virais - Revisão da Literatura
Principles of viral vector-based gene therapy - A Literature Review
DOI:
https://doi.org/10.47456/hb.64.50214Palavras-chave:
agentes de terapia gênica, terapia genética, terapia somática de genes, vetores virais, vírusResumo
Nas últimas quatro décadas os avanços da biologia molecular transformaram o papel dos vírus, deixando o papel comumente atribuído de “vilões” para se tornarem agentes fundamentais dentro de estratégias terapêuticas sofisticadas. A terapia gênica baseada em vetores virais emerge da investigação minuciosa desses organismos, junto do constante aprimoramento das técnicas de biologia molecular, visando ampliar o escopo terapêutico de condições intimamente ligadas a disfunções genéticas e quadros infecciosos que carecem de tratamentos convencionais eficazes. A terapia gênica inaugura um novo paradigma no desenvolvimento de vacinas: as vacinas genéticas, que, explorando os mecanismos complexos de transferência e regulação gênicas, podem induzir não apenas respostas imunes específicas, mas também alterações fisiológicas complexas e sistêmicas, ampliando o leque de abordagens terapêuticas para diversas doenças. Esta revisão tem como objetivo consolidar os conhecimentos virológicos fundamentais que sustentam o uso de vírus na terapia gênica, além de apresentar os vetores virais mais proeminentes utilizados até o momento e suas respectivas aplicações clínicas.
Referências
1. ALI S, MUMTAZ S, SHAKIR HA, KHAN M, TAHIR HM, MUMTAZ S, MUGHAL TA, HASSAN A, KAZMI SAR, SADIA, IRFAN M, KHAN MA. Current status of beta‐thalassemia and its treatment strategies. Mol Genet Genomic Med 9(12): e1788, 2021.
2. ALTAN-BONNET N, PANIGRAHI M. Nonlytic egress and transmission in the virus world. Annu Rev Biochem 94(1): 531-560, 2025.
3. ANVISA. AGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA. Aprovado primeiro produto de terapia avançada no Brasil. Brasília, 06 ago. 2020. Disponível em: https://www.gov.br/anvisa/pt-br/assuntos/noticias-anvisa/2020/aprovado-primeiro-produto-de-terapia-avancada-no-brasil. Acesso em 27 dezembro de 2025.
4. ARABI F, MANSOURI V, AHMADBEIGI N. Gene therapy clinical trials, where do we go? An overview. Biomed Pharmacother 153: 113324, 2022.
5. BEDWELL GJ, ENGELMAN AN. Factors That Mold the Nuclear Landscape of HIV-1 Integration. Nucleic Acids Res 49(2): 621-635, 2021.
6. BUDZIK KM, NACE RA, IKEDA Y, RUSSEL SJ. Oncolytic Foamy Virus: Generation and Properties of a Nonpathogenic Replicating Retroviral Vector System That Targets Chronically Proliferating Cancer Cells. J Virol 95(10): e00015-21, 2021.
7. BULCHA JT, WANG Y, MA H, TAI PWL, GAO G. Viral vector platforms within the gene therapy landscape. Signal Transduct Target Ther 6(1): 53, 2021.
8. CETIN B, ERENDOR F, EKSI YE, SANLIOGLU AD, SANLIOGLU S. Gene and Cell Therapy of Human Genetic diseases: Recent Advances and Future Directions. J Cell Mol Med 28(17): e70056, 2024.
9. CHAMEETTACHAL A, MUSTAFA F, RIZVI TA. Understanding Retroviral Life Cycle and its Genomic RNA Packaging. J Mol Biol 435(3): 167924, 2023.
10. CHEN S, HSIEH Y, TZENG H, LIN C, HSU K, CHIANG Y, LIN S, SU M, HSIEH W, LEE C. ABL Genomic Editing Sufficiently Abolishes Oncogenesis of Human Chronic Myeloid Leukemia Cells In Vitro and In Vivo. Cancers 12(6): 1399, 2020.
11. CHEN YH, KEISER MS, DAVIDSON BL. Viral Vectors for Gene Transfer. Curr Protoc Mouse Biol 8(4): e58, 2018.
12. CHO H, JANG Y, PARK K, CHOI H, NOWAKOWSKA A, LEE H, KIM M, KANG M, KIM J, SHIN HY, OH Y, KIM YB. Human endogenous retrovirus-enveloped baculoviral DNA vaccines against MERS-CoV and SARS-CoV2. NPJ Vaccines 6(37): 2021. https://doi.org/10.1038/s41541-021-00303-w
13. COMISEL RM, KARA B, FIESSER FH, FARID SS. Gene therapy process change evaluation framework: Transient transfection and stable producer cell line comparison. Biochem Eng J 176: 2021. https://doi.org/10.1016/j.bej.2021.108202.
14. CRING MR, SHEFFIELD VC. Gene Therapy and Gene correction: targets, progress, and Challenges for Treating Human Diseases. Gene Ther 29(1-2): 3-12, 2022.
15. DODGE MJ, MACNEIL KM, TESSIER TM, WEINBERG JB, MYMRYK JS. Emerging antiviral therapeutics for human adenovirus infection: Recent developments and novel strategies. Antiviral Res 188: 105034, 2021.
16. DUVERGÉ A, NEGRONI M. Pseudotyping Lentiviral Vectors: When the Clothes Make the Virus. Viruses 12(11): 1311, 2020.
17. EL-BATTARI A, RODRIGUEZ L, CHAHINIAN H, DELÉZAY O, FANTINI J, YAHI N, Di SCALA C. Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells. Int J Mol Sci 22(21): 11550, 2021.
18. EMA. EUROPEAM MEDICINES AGENCY. Luxturna (Voretigene neparvovec), 2018. EPAR. European Public Assessement Report. Amsterdam: Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/luxturna. Accessed on July 15, 2025.
19. EMA. EUROPEAN MEDICINES AGENCY. Imlygic, 2024. EPAR. European Public Assessment Report. Amsterdam: Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/imlygic. Accessed on July 15, 2025.
20. FDA. FOOD AND DRUG ADMINISTRATION. Luxturna (voretigene neparvovec-rzyl) - gene therapy for RPE65 mutation-associated retinal dystrophy. Silver Spring, MD: FDA, 18 dez. 2017 (approval history). Available from: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna. Accessed on July 15, 2025.
21. FDA. FOOD AND DRUG ADMINISTRATION. Approval Letter. IMLYGIC (Talimogene Laherparepvec). Silver Spring: FDA, 2023. Available from: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/imlygic. Accessed on July 15, 2025.
22. FERRUA F, AIUTI A. Twenty-Five Years of Gene Therapy for ADA-SCID: from Bubble Babies to an Approved Drug. Hum Gene Ther 28(11): 972-981, 2017.
23. GALLARDO J, PÉREZ-ILLANA M, MARTÍN-GONZÁLEZ N, SAN MARTÍN C. Adenovirus Structure: What Is New? Int J Mol Sci 22(10): 5240, 2021.
24. GHOSH S, BROWN AM, JENKINS C, CAMPBELL K. Viral Vector Systems for Gene Therapy: a Comprehensive Literature Review of Progress and Biosafety Challenges. Appl Biosaf 25(1): 7-18, 2020.
25. GHALEH HEG, BOLANDIAN M, DOROSTKAR R, JAFARI A, POUR MF. Concise Review on Optimized Methods in Production and Transduction of Lentiviral Vectors in Order to Facilitate Immunotherapy and Gene Therapy. Biomed Pharmacother 128: 110276, 2020.
26. GREBER UF, GÓMEZ-GONZÁLEZ A. Adenovirus - a Blueprint for Gene Delivery. Curr Opin Virol 48: 49-56, 2021.
27. GUIMARAES TAC, GEORGIOU M, BAINBRIDGE JWB, MICHAELIDES M. Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. Br J Ophthalmol 105(2): 151-157, 2020.
28. GUTIERREZ-GUERRERO A, COSSET F, VERHOEYEN E. Lentiviral Vector Pseudotypes: Precious Tools to Improve Gene Modification of Hematopoietic Cells for Research and Gene Therapy. Viruses 12(9): 1016, 2020.
29. HART KL, LIU B, BROWN D, CAMPO-FERNANDEZ B, TAM K, ORR K, HOLLIS RP, BRENDEL C, WILLIAMS DA, KOHN DB. A novel high-titer, bifunctional lentiviral vector for autologous hematopoietic stem cell gene therapy of sickle cell disease. Mol Ther Methods Clin Dev 32(2): 101254, 2024.
30. HSIEH MH, BONNER M, PIERCIEY FJ, UCHIDA N, ROTTMAN J, DEMOPOULUS L, SCHMIDT M, KANTER J, WALTERS MC, THOMPSON AA, ASMAL M, TISDALE JF. Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease. Blood Adv 4(9): 2058-2063, 2020.
31. ISLAM A, TOM VJ. The Use of Viral Vectors to Promote Repair after Spinal Cord Injury. Exp Neurology 354: 114102, 2022.
32. KAKOTY V, SARATHLAL KC, DUBEY SK, YANG CH, KESHARWANI P, TALIYAN R. Lentiviral mediated gene delivery as an effective therapeutic approach for Parkinson disease. Neurosci Lett 750: 135769, 2021.
33. KHAN A, RIAZ R, SAAD A, AKILIMALI A. Revolutionary breakthrough: FDA Approves Vyjuvektm, the First Topical Gene Therapy for Dystrophic Epidermolysis Bullosa. Ann Med Surg 85(12): 6298-6301, 2023.
34. KITAWI R, LEDGER S, KELLEHER AD, AHLENSTIEL CL. Advances in HIV Gene Therapy. Int J Mol Sci 25(5): 2771, 2024.
35. KOHN DB, BOOTH C, SHAW KL, XU-BAYFORD J, GARABEDIAN E, TREVISAN V, CARBONARO-SARRACINO DA, SONI K, TERRAZAS D, SNELL K, IKEDA A, LEON-RICO D, MOORE TB, BUCKLAND KF, SHAH AJ, GILMOUR KC, DE OLIVEIRA S, RIVAT C, CROOKS GM, IZOTOVA N, TSE J, ADAMS S, SHUPIEN S, RICKETTS H, DAVILA A, UZOWURU C, ICREVERZI A, BARMAN P, CAMPO FERNANDEZ B, HOLLIS RP, CORONEL M, YU A, CHUN KM, CASAS CE, ZHANG R, ARDUINI S, LYNN F, KUDARI M, SPEZZI A, ZAHN M, HEIMKE R, LABIK I, PARROTT R, BUCKLEY RH, REEVES L, CORNETTA K, SOKOLIC R, HERSHFIELD M, SCHMIDT M, CANDOTTI F, MALECH HL, THRASHER AJ, GASPAR HB. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. N Engl J Med 384(21): 2002-2013, 2021.
36. KOHN DB, CHEN YY, SPENCER MJ. Successes and Challenges in Clinical Gene Therapy. Gene Ther 30(10-11): 738-746, 2023.
37. KOONIN EV, KRUPOVIC M, AGOL VI. The Baltimore Classification of Viruses 50 Years Later: How Does It Stand in the Light of Virus Evolution? Microbiol Mol Biol Rev 85(3): e0005321, 2021.
38. KU MW, AUTHIÉ P, NEVO F, SOUQUE P, BOURGINE M, ROMANO M, CHARNEAU P, MAJLESSI L. Lentiviral vector induces high-quality memory T cells via dendritic cells transduction. Commun Biol 4(1): 713, 2021.
39. LEBORGNE C, BARBON E, ALEXANDER JM, HANBY H, DELIGNAT S, COHEN DM, COLLAUD F, MURALEETHARAN S, LUPO D, SILVERBERG J, HUANG K, VAN WITTENGERGHE L, MAROLLEAU B, MIRANDA A, FABIANO A, DAVENTURE V, BECK H, ANGUELA XM, RONZITTI G, ARMOUR SM, LACROIX-DESMAZES S, MINGOZZI F. IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies. Nat Med 26(7): 1096-1101, 2020.
40. LI C, SAMULSKI RJ. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet 21(4): 255-272, 2020.
41. LI X, LE Y, ZHANG Z, NIAN X, LIU B, YANG X. Viral Vector-Based Gene Therapy. Int J Mol Sci 24(9): 7736, 2023.
42. LUNDSTROM K. Viral vectors in gene therapy. Dis Basel Switz 6(2): 42, 2018. DOI: 10.3390/diseases6020042.
43. MAETZIG T, GALLA M, BAUM C, SCHAMBACH A. Gammaretroviral Vectors: Biology, Technology and Application. Viruses 3(6): 677-713, 2011.
44. MALDONADO MD, ROMERO-AIBAR J, PÉREZ-SAN-GREGORIO MA. COVID-19 Pandemic as a Risk Factor for the Reactivation of Herpes Viruses. Epidemiol Infect 149: e173, 2021.
45. MANDALAWAITTA HP, RAJENDRA KC, FAIRFAX K, HEWITT AW. Emerging trends in virus and virus-like particle gene therapy delivery to the brain. Mol. Ther. Nucleic Acids 35(3): 102280, 2024.
46. MARTUZA RL, MALICK A, MARKERT JM, RUFFNER KL, COEN DM. Experimental Therapy of Human Glioma by Means of a Genetically Engineered Virus Mutant. Science 252(5007): 854-856, 1991.
47. MEHMETOGLU-GURBUZ T, YEH R, GARG H, JOSHI A. Combination gene therapy for HIV using a conditional suicidal gene with CCR5 knockout. Virol J 18(1): 31, 2021.
48. MEROLA A, VAN LAAR A, LONSER R, BANKIEWICZ K. Gene therapy for Parkinson’s disease: contemporary practice and emerging concepts. Expert Rev Neurother 20(6): 577-590, 2020.
49. MILANI M, CANEPARI C, LIU T, BIFFI M, RUSSO F, PLATI T, CURTO R, PATARROYO-WHITE S, DRAGER D, VISIGALLI I, BROMBIN C, ALBERTINI P, FOLLENZI A, AYUSO E, MUELLER C, ANNONI A, NADINI L, CANTORE A. Liver-directed lentiviral gene therapy corrects hemophilia A mice and achieves normal-range factor VIII activity in non-human primates. Nat Commun 13: 2454, 2022.
50. MODY PH, PATHAK S, HANSON LK, SPENCER JV. Herpes Simplex Virus: a Versatile Tool for Insights into Evolution, Gene Delivery, and Tumor Immunotherapy. Virol 11: 1178122X2091327, 2020.
51. NUALKAEW T, SII-FELICE K, GIORGI M, MCCOLL B, GOUZIL J, GLASER A, VOON HPJ, TEE HY, GRIGORIADIS G, SVASTI S, FUCHAROEN S, HONGENG S, LEBOUICH P, PAYEN E, VADOLAS J. Coordinated β-globin expression and α2-globin reduction in a multiplex lentiviral gene therapy vector for β-thalassemia. Mol Ther 29(9): 2841-2853, 2021.
52. PAGANI I, DEMELA P, GHEZZI S, VICENZI E, PIZZATO M, POLI G. Host Restriction Factors Modulating HIV Latency and Replication in Macrophages. Int J Mol Sci 23(6): 3021, 2022.
53. PARVEZ MK. Geometric Architecture of Viruses. World J Virol 9(2): 5-18, 2020.
54. POLETTI V, MAVILIO F. Designing Lentiviral Vectors for Gene Therapy of Genetic Diseases. Viruses 13(8): 1526, 2021.
55. RITTINER JE, MONCALVO M, CHIBA-FALEK O, KANTOR B. Gene-Editing Technologies Paired With Viral Vectors for Translational Research Into Neurodegenerative Diseases. Front Mol Neurosci 13: 148, 2020.
56. ROGERS GL, CANNON PM. Genome Edited B cells: a New Frontier in Immune Cell Therapies. Mol Ther 29(11): 3192-3204, 2021.
57. SANT'ANNA TB, ARAUJO NM. Adeno-associated Virus Infection and Its Impact in Human health: an Overview. Virol J 19(173): 2022. DOI: 10.1186/s12985-022-01900-4.
58. SANTOS, NORMA SUELY DE OLIVEIRA; ROMANOS, MARIA TERESA; WIGG, MARCIA; COUCEIRO, JOSÉ NELSON. Estrutura viral e composição dos vírus. In: SANTOS NOS, ROMANOS MT, WIGG M, COUCEIRO JN. Virologia Humana, 4.ed., Rio de Janeiro: Guanabara Koogan, 2021, p.23-45.
59. SAWAISORN P, ATJANASUPPAT K, UAESOONTRACHOON K, RATTANANON P, TREESUPPHARAT W, HONGENG S, ANURATHAPAN U. Comparison of the Efficacy of Second and Third Generation Lentiviral Vector Transduced CAR CD19 T Cells for Use in the Treatment of Acute Lymphoblastic Leukemia Both in Vitro and in Vivo Models. PLoS One 18(2): e0281735, 2023.
60. SAYED N, ALLAWADHI P, KHURANA A, SINGH V, NAVIK U, PASUMARTHI SK, KHURANA I, BANOTHU AK, WEISKIRCHEN R, BHARANI KK. Gene therapy: Comprehensive Overview and Therapeutic Applications. Life Sci 294: 120375, 2022.
61. SECORD E, HARTOG NL. Review of Treatment for Adenosine Deaminase Deficiency (ADA) Severe Combined Immunodeficiency (SCID). Ther Clin Risk Manag 18: 939-944, 2022.
62. SHIRLEY JL, DE JONG YP, TERHORST C, HERZOG RW. Immune Responses to Viral Gene Therapy Vectors. Mol Ther 28(3): 709-722, 2020.
63. SWEENEY NP, VINK CA. The impact of lentiviral vector genome size and producer cell genomic to gag-pol mRNA ratios on packaging efficiency and titre. Mol Ther Methods Clin Dev 21: 574-584, 2021.
64. TANHEHCO YC. Gene Therapy for Hemoglobinopathies. Transfus Apher Sci 60(1): 103061, 2021.
65. TEBBI CK. Sickle Cell Disease, a Review. Hemato 3(2): 341-366, 2022.
66. TRIVEDI PD, BYRNE BJ, CORTI M. Evolving Horizons: Adenovirus Vectors’ Timeless Influence on Cancer, Gene Therapy and Vaccines. Viruses 15(12): 2378, 2023.
67. VEENHUIS RT, ABREU CM, SHIRK EN, GAMA L, CLEMENTS JE. HIV replication and latency in monocytes and macrophages. Semin Immunol 51: 101472, 2021.
68. VERZOSA AL, MCGEEVER LA, BHARK S-J, DELGADO T, SALAZAR N, SANCHEZ EL. Herpes Simplex Virus 1 Infection of Neuronal and Non-Neuronal Cells Elicits Specific Innate Immune Responses and Immune Evasion Mechanisms. Front Immunol 12: 644334, 2021.
69. WANG D, WANG K, CAI Y. An overview of development in gene therapeutics in China. Gene Ther 27(7-8): 338-348, 2020.
70. WANG J-H, GESSLER DJ, ZHAN W, GALLAGHER TL, GAO G. Adeno-associated Virus as a Delivery Vector for Gene Therapy of Human Diseases. Signal Transduct Target Ther 9: 78, 2024.
71. WANG X, MA C, RODRÍGUEZ LABRADA R, QIN Z, XU T, HE Z, WEI Y. Recent advances in lentiviral vectors for gene therapy. Sci China Life Sci 64(11): 1842-1857, 2021.
72. WANG Y, BRUGGEMAN KF, FRANKS S, GAUTAM V, HODGETTS SI, HARVEY AR, WILLIAMS RJ, NISBET DR. Is Viral Vector Gene Delivery More Effective Using Biomaterials? Adv Healthc Mater 10(1): e2001238, 2020.
73. WATANABE M, NISHIKAWAJI Y, KAWAKAMI H, KOSAI K. Adenovirus Biology, Recombinant Adenovirus, and Adenovirus Usage in Gene Therapy. Viruses 13(12): 2502, 2021.
74. WINGO TS, LIU Y, GERASIMOV ES, VATTATHIL SM, WYNNE ME, LIU J, LORI A, FAUNDEZ V, BENNETT DA, SEYFRIED NT, LEVEY AI, WINGO AP. Shared Mechanisms across the Major Psychiatric and Neurodegenerative Diseases. Nat Commun 13: 4314, 2022.
75. YAHYA EB, ALQADHI AM. Recent Trends in Cancer therapy: a Review on the Current State of Gene Delivery. Life Sci 269: 119087, 2021.
76. YODER KE, RABE AJ, FISHEL R, LARUE RC. Strategies for Targeting Retroviral Integration for Safer Gene Therapy: Advances and Challenges. Front Mol Biosci 8: 644294, 2021.
77. ZENGEL J, CARETTE JE. Structural and Cellular Biology of adeno-associated Virus Attachment and Entry. Adv Virus Res 106: 39-84, 2020.
78. ZHANG W-W, LI L, LI D, LIU J, LI X, LI W, XU X, ZHANG MJ, CHANDLER LA, LIN H, HU A, XU W, LAM DM-K. The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic. Hum Gene Ther 29(2): 160-179, 2018.
79. ZHAO Z, ANSELMO AC, MITRAGOTRI S. Viral Vector‐based Gene Therapies in the Clinic. Bioeng Transl Med 7(1): e10258, 2021.
80. ZHU S, VIEJO-BORBOLLA A. Pathogenesis and Virulence of Herpes Simplex Virus. Virulence 12(1): 2670-2702, 2021.
81. ZITTERSTEIJN HA, GONÇALVES MAFV, HOEBEN RC. A primer to gene therapy: Progress, prospects, and problems. J Inherit Metab Dis 44(1): 54-71, 2020.
Downloads
Publicado
Edição
Seção
Licença
Copyright (c) 2025 Leandro Alves Inojosa Filho, Beatriz de Albuquerque Vilar, Gabriela Souto Vieira de Mello
Este trabalho está licenciado sob uma licença Creative Commons Attribution 4.0 International License.
Todos os trabalhos publicados na Brazilian Journal of Production Engineering (BJPE) estão licenciados sob a Creative Commons Atribuição 4.0 Internacional (CC BY 4.0).
Isso significa que:
-
Qualquer pessoa pode copiar, distribuir, exibir, adaptar, remixar e até utilizar comercialmente os conteúdos publicados na revista;
-
Desde que sejam atribuídos os devidos créditos aos autores e à BJPE como fonte original;
-
Não é exigida permissão adicional para reutilização, desde que respeitados os termos da licença.
Esta política está em conformidade com os princípios do acesso aberto, promovendo a ampla disseminação do conhecimento científico.
