The Past, Present, and Future of Gene Therapy
DOI:
https://doi.org/10.47611/jsrhs.v12i3.4849Keywords:
Gene Engineering, Gene Therapy, CRISPR-Cas9, CAR-T Cell, Adeno-associated VirusAbstract
Since 2010, gene therapy has rapidly gained interest as a possible method to cure previously untouchable and incurable diseases. The idea of tackling the disease at its genetic core to prevent the malignance from manifesting in the first place seemed unrealistic at first, but decades of research have started to bear fruit and these untouchable diseases suddenly seem mortal. CRISPR-Cas9, Chimeric Antigen Receptor (CAR) T-cell therapy, and adeno-associated virus (AAV) therapy utilize different gene engineering techniques to nullify previously incurable diseases. This paper serves as a comprehensive review paper which analyzes the mechanism, advantages, and disadvantages of these three gene therapy techniques. This paper states the genetic scissor mechanism of the CRISPR-Cas9 complex, and its difference from its predecessors, the artificial tinkering of the CAR t-cell therapy method and its subsequent utilization of the host’s immune system, and finally the transduction potential of the AAV gene therapy. Finally, this paper states the current status and clinical application of the three gene therapy techniques, including their medication terminology and target diseases, and helps elucidate the future and potential of these three gene therapy techniques.
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Aiuti, A., Roncarolo, M. G., & Naldini, L. (2017). Gene therapy for ada‐scid, the first marketing approval of an ex vivo gene therapy in Europe: Paving the road for the next generation of Advanced Therapy Medicinal Products. EMBO Molecular Medicine, 9(6), 737–740. https://doi.org/10.15252/emmm.201707573
AlDallal, S. (2020). Yescarta: A New Era for Non-Hodgkin Lymphoma Patients. Cureus. https://doi.org/10.7759/cureus.11504
Allan, K. M., Farrow, N., Donnelley, M., Jaffe, A., & Waters, S. A. (2021). Treatment of cystic fibrosis: From gene- to cell-based therapies. Frontiers in Pharmacology, 12. https://doi.org/10.3389/fphar.2021.639475
Atchison, R. W., Casto, B. C., & Hammon, W. McD. (1965). Adenovirus-associated defective virus particles. Science, 149(3685), 754–756. https://doi.org/10.1126/science.149.3685.754
Büning, H. (2013). Gene therapy enters the Pharma Market: The short story of a long journey. EMBO Molecular Medicine, 5(1), 1–3. https://doi.org/10.1002/emmm.201202291
Center for Biologics Evaluation and Research (CBER). (2018). What is gene therapy? U.S. Food and Drug Administration. Retrieved April 13, 2023, from https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy#footnote1
Center for Biologics Evaluation and Research (CBER). (2022) Kymriah (tisagenlecleucel). U.S. Food and Drug Administration. Retrieved April 13, 2023, from https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel
Cheung, A. K., Hoggan, M. D., Hauswirth, W. W., & Berns, K. I. (1980). Integration of the adeno-associated virus genome into cellular DNA in latently infected human Detroit 6 cells. Journal of virology, 33(2), 739–748. https://doi.org/10.1128/JVI.33.2.739-748.1980
Christian, M., Cermak, T., Doyle, E. L., Schmidt, C., Zhang, F., Hummel, A., Bogdanove, A. J., & Voytas, D. F. (2010). Targeting DNA double-strand breaks with TAL effector nucleases. Genetics, 186(2), 757–761. https://doi.org/10.1534/genetics.110.120717
Cohen, S. N., Chang, A. C., Boyer, H. W., & Helling, R. B. (1973). Construction of biologically functional bacterial plasmids in vitro. Proceedings of the National Academy of Sciences, 70(11), 3240–3244. https://doi.org/10.1073/pnas.70.11.3240
Colella, P., Ronzitti, G., & Mingozzi, F. (2018). Emerging issues in AAV-mediated in vivo gene therapy. Molecular Therapy - Methods & Clinical Development, 8, 87–104. https://doi.org/10.1016/j.omtm.2017.11.007
Cooney, A., McCray, P., & Sinn, P. (2018). Cystic fibrosis gene therapy: Looking back, looking forward. Genes, 9(11), 538. https://doi.org/10.3390/genes9110538
Cyranoski, D. (2016). CRISPR gene-editing tested in a person for the first time. Nature 539, 479. https://doi.org/10.1038/nature.2016.20988
Deverman, B. E., Ravina, B. M., Bankiewicz, K. S., Paul, S. M., & Sah, D. W. Y. (2018). Gene therapy for neurological disorders: progress and prospects. Nature reviews. Drug discovery, 17(9), 641–659. https://doi.org/10.1038/nrd.2018.110
Dunbar, C. E., High, K. A., Joung, J. K., Kohn, D. B., Ozawa, K., & Sadelain, M. (2018). Gene therapy comes of age. Science (New York, N.Y.), 359(6372), eaan4672. https://doi.org/10.1126/science.aan4672
FDA. (2018). What is gene therapy?. U.S. Food and Drug Administration. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy
Hastie, E., & Samulski, R. J. (2015). Adeno-associated virus at 50: a golden anniversary of discovery, research, and gene therapy success--a personal perspective. Human gene therapy, 26(5), 257–265. https://doi.org/10.1089/hum.2015.025
Hoggan, M. D., Blacklow, N. R., & Rowe, W. P. (1966). Studies of small DNA viruses found in various adenovirus preparations: physical, biological, and immunological characteristics. Proceedings of the National Academy of Sciences of the United States of America, 55(6), 1467–1474. https://doi.org/10.1073/pnas.55.6.1467
Ishikawa, K., Weber, T., & Hajjar, R. J. (2018). Human Cardiac Gene Therapy. Circulation research, 123(5), 601–613. https://doi.org/10.1161/CIRCRESAHA.118.311587
Khan, S. H. (2019). Genome-editing technologies: Concept, Pros, and cons of various genome-editing techniques and bioethical concerns for clinical application. Molecular Therapy - Nucleic Acids, 16, 326–334. https://doi.org/10.1016/j.omtn.2019.02.027
Kotterman, M. A., Chalberg, T. W., & Schaffer, D. V. (2015). Viral vectors for gene therapy: Translational and clinical outlook. Annual Review of Biomedical Engineering, 17(1), 63–89. https://doi.org/10.1146/annurev-bioeng-071813-104938
Klug, A. (2010). The discovery of zinc fingers and their applications in gene regulation and genome manipulation. Annual Review of Biochemistry, 79(1), 213–231. https://doi.org/10.1146/annurev-biochem-010909-095056
Kite Pharma. (2020). Yescarta® (Axicabtagene Ciloleucel) demonstrates high rates of response in relapsed or refractory indolent Non-Hodgkin lymphoma. Kite Pharma, Changing the Way Cancer is Treated. https://www.kitepharma.com/news/press-releases/2020/5/yescarta-axicabtagene-ciloleucel-demonstrates-high-rates-of-response-in-relapsed-or-refractory-indolent-nonhodgkin-lymphoma
Kim, Y. G., Cha, J., & Chandrasegaran, S. (1996). Hybrid restriction enzymes: Zinc finger fusions to fok I cleavage domain. Proceedings of the National Academy of Sciences, 93(3), 1156–1160. https://doi.org/10.1073/pnas.93.3.1156
Li, C., & Samulski, R. J. (2020). Engineering adeno-associated virus vectors for gene therapy. Nature reviews. Genetics, 21(4), 255–272. https://doi.org/10.1038/s41576-019-0205-4
Li, T., & Yang, B. (2013). Tal effector nuclease (talen) engineering. Methods in Molecular Biology, 63–72. https://doi.org/10.1007/978-1-62703-293-3_5
Li, T., Yang, Y., Qi, H., Cui, W., Zhang, L., Fu, X., He, X., Liu, M., Li, P.-feng, & Yu, T. (2023). CRISPR/Cas9 Therapeutics: Progress and Prospects. Signal Transduction and Targeted Therapy, 8(1). https://doi.org/10.1038/s41392-023-01309-7
Locke, F. L., Neelapu, S. S., Bartlett, N. L., Lekakis, L. J., Miklos, D., Jacobson, C. A., Braunschweig, I., Oluwole, O., Siddiqi, T., Lin, Y., Timmerman, J., Friedberg, J. W., Bot, A., Rossi, J., Navale, L., Jiang, Y., Aycock, J., Elias, M., Wiezorek, J., & Go, W. Y. (2017). Abstract CT019: Primary results from Zuma-1: A pivotal trial of Axicabtagene Ciloleucel (axicel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Cancer Research, 77(13_Supplement). https://doi.org/10.1158/1538-7445.am2017-ct019
Lu, Y., Xue, J., Deng, T., Zhou, X., Yu, K., Deng, L., Huang, M., Yi, X., Liang, M., Wang, Y., Shen, H., Tong, R., Wang, W., Li, L., Song, J., Li, J., Su, X., Ding, Z., Gong, Y., Zhu, J., … Mok, T. (2020). Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer. Nature medicine, 26(5), 732–740. https://doi.org/10.1038/s41591-020-0840-5
Lulla, P. D., Hill, L. C., Ramos, C. A., & Heslop, H. E. (2018). The use of chimeric antigen receptor T cells in patients with non-Hodgkin lymphoma. Clinical advances in hematology & oncology : H&O, 16(5), 375–386.
Lundstrom, K. (2018). Viral Vectors in Gene Therapy. Diseases, 6(2), 42. https://doi.org/10.3390/diseases6020042
Mali, P., Esvelt, K. M., & Church, G. M. (2013). Cas9 as a versatile tool for engineering biology. Nature Methods, 10(10), 957–963. doi:10.1038/nmeth.2649
Malzahn, A., Zhang, Y., & Qi, Y. (2019). CRISPR-Act2.0: An Improved Multiplexed System for Plant Transcriptional Activation. Methods in molecular biology (Clifton, N.J.), 1917, 83–93. https://doi.org/10.1007/978-1-4939-8991-1_7
Mak, A. N.-S., Bradley, P., Bogdanove, A. J., & Stoddard, B. L. (2013). Tal effectors: Function, structure, engineering and applications. Current Opinion in Structural Biology, 23(1), 93–99. https://doi.org/10.1016/j.sbi.2012.11.001
Maude, S. L., Laetsch, T. W., Buechner, J., Rives, S., Boyer, M., Bittencourt, H., Bader, P., Verneris, M. R., Stefanski, H. E., Myers, G. D., Qayed, M., De Moerloose, B., Hiramatsu, H., Schlis, K., Davis, K. L., Martin, P. L., Nemecek, E. R., Yanik, G. A., Peters, C., Baruchel, A., … Grupp, S. A. (2018). Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. The New England journal of medicine, 378(5), 439–448. https://doi.org/10.1056/NEJMoa1709866
Moore, N. A., Morral, N., Ciulla, T. A., & Bracha, P. (2017). Gene therapy for inherited retinal and optic nerve degenerations. Expert Opinion on Biological Therapy, 18(1), 37–49. https://doi.org/10.1080/14712598.2018.1389886
National Cancer Institute (NCI). (2023). Car T cells: Engineering immune cells to treat cancer. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
Neelapu, S. S., Dickinson, M., Munoz, J., Ulrickson, M. L., Thieblemont, C., Oluwole, O. O., Herrera, A. F., Ujjani, C. S., Lin, Y., Riedell, P. A., Kekre, N., de Vos, S., Lui, C., Milletti, F., Dong, J., Xu, H., & Chavez, J. C. (2022). Axicabtagene CILOLEUCEL as first-line therapy in high-risk large B-cell lymphoma: The phase 2 zuma-12 trial. Nature Medicine, 28(4), 735–742. https://doi.org/10.1038/s41591-022-01731-4
Normile, D. (2018). CRISPR bombshell: Chinese researcher claims to have created gene-edited twins. https://www.science.org/content/article/crispr-bombshell-chinese-researcher-claims-have-created-gene-edited-twins
Ogbonmide, T., Rathore, R., Rangrej, S. B., Hutchinson, S., Lewis, M., Ojilere, S., Carvalho, V., & Kelly, I. (2023). Gene Therapy for Spinal Muscular Atrophy (SMA): A Review of Current Challenges and Safety Considerations for Onasemnogene Abeparvovec (Zolgensma). Cureus, 15(3), e36197. https://doi.org/10.7759/cureus.36197
OHSU. (2023). CAR T-Cell Therapy for Cancer. OHSU. https://www.ohsu.edu/knight-cancer-institute/car-t-cell-therapy-cancer
Pan, C., Wu, X., Markel, K., Malzahn, A. A., Kundagrami, N., Sretenovic, S., Zhang, Y., Cheng, Y., Shih, P. M., & Qi, Y. (2021). CRISPR–act3.0 for highly efficient multiplexed gene activation in plants. Nature Plants, 7(7), 942–953. https://doi.org/10.1038/s41477-021-00953-7
Razin, S. V., Borunova, V. V., Maksimenko, O. G., & Kantidze, O. L. (2012). Cys2His2 zinc finger protein family: Classification, functions, and major members. Biochemistry (Moscow), 77(3), 217–226. https://doi.org/10.1134/s0006297912030017
Rose, J. A., Berns, K. I., Hoggan, M. D., & Koczot, F. J. (1969). Evidence for a single-stranded adenovirus-associated virus genome: formation of a DNA density hybrid on release of viral DNA. Proceedings of the National Academy of Sciences of the United States of America, 64(3), 863–869. https://doi.org/10.1073/pnas.64.3.863
Sack, B. K., & Herzog, R. W. (2009). Evading the immune response upon in vivo gene therapy with viral vectors. Current opinion in molecular therapeutics, 11(5), 493–503.
Sadelain, M., Brentjens, R., & Rivière, I. (2013). The basic principles of chimeric antigen receptor design. Cancer Discovery, 3(4), 388–398. https://doi.org/10.1158/2159-8290.cd-12-0548
Samulski, R. J., Chang, L. S., & Shenk, T. (1989). Helper-free stocks of recombinant adeno-associated viruses: normal integration does not require viral gene expression. Journal of virology, 63(9), 3822–3828. https://doi.org/10.1128/JVI.63.9.3822-3828.1989
Sterner, R. C., & Sterner, R. M. (2021). Car-T cell therapy: Current limitations and potential strategies. Blood Cancer Journal, 11(4). https://doi.org/10.1038/s41408-021-00459-7
Stieger, K., Lheriteau, E., Moullier, P., & Rolling, F. (2009). Aav-mediated gene therapy for retinal disorders in large animal models. ILAR Journal, 50(2), 206–224. https://doi.org/10.1093/ilar.50.2.206
Uddin, F., Rudin, C. M., & Sen, T. (2020). CRISPR gene therapy: Applications, limitations, and implications for the future. Frontiers in Oncology, 10. https://doi.org/10.3389/fonc.2020.01387
Urnov, F. D., Rebar, E. J., Holmes, M. C., Zhang, H. S., Gregory, P. D. (2010). Genome editing with engineered zinc finger nucleases. Nature Reviews Genetics, 11(9), 636–646. https://doi.org/10.1038/nrg2842
Wang, H., Yang, H., Shivalila, C. S., Dawlaty, M. M., Cheng, A. W., Zhang, F., & Jaenisch, R. (2013). One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell, 153(4), 910–918. https://doi.org/10.1016/j.cell.2013.04.025
Wu, Z., Asokan, A., & Samulski, R. J. (2006). Adeno-associated virus serotypes: vector toolkit for human gene therapy. Molecular therapy : the journal of the American Society of Gene Therapy, 14(3), 316–327. https://doi.org/10.1016/j.ymthe.2006.05.009
Yourgenome (2017, August 23). What is genome editing? @yourgenome · Science website. Retrieved April 13, 2023, from https://www.yourgenome.org/facts/what-is-genome-editing/
Zhang, X., Lu, L., Song, Q., Yang, Q., Li, D., Sun, J., Li, T., & Cong, P. (2013). DomHR: Accurately identifying domain boundaries in proteins using a hinge region strategy. PLoS ONE, 8(4). https://doi.org/10.1371/journal.pone.0060559
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