Advancing Gene Therapy in Sickle Cell Disease
Exploring the Potential of Prime Editing
DOI:
https://doi.org/10.58445/rars.1613Keywords:
Sickle Cell Disease, Prime Editing, Gene Therapy, CRISPR-Cas9, Red Blood Cells, HBB Gene, Genetic MutationAbstract
Sickle cell disease (SCD) is a prevalent genetic disorder caused by a mutation in the HBB gene, leading to the production of abnormal hemoglobin that can block blood flow and cause severe pain. While conventional treatments for SCD are available, they have several limitations and are often not curative. As a result, gene therapy has emerged as a promising alternative for SCD treatment. CASGEVY, a gene therapy using CRISPR-Cas9 technology, has shown success in reducing symptoms of SCD by knocking out BCL11A and increasing fully functional, fetal hemoglobin. However, CASGEVY is prohibitively expensive and has some risks and inconveniences that limit its broader use. Prime editing, a newer gene editing technique, is considered more precise and potentially safer as it can be used to directly correct the HBB mutation. Additionally, unlike CASGEVY, prime editing could be used in vivo to correct the SCD mutation within the bone marrow. Recent studies have shown that prime editing can effectively correct the mutation both ex vivo and in vivo. Since in vivo prime editing could be more practical and affordable for people around the world, including in sub-Saharan Africa where SCD is most common, further research is needed to improve the efficiency and safety of prime editing to make it applicable to patients suffering from SCD globally. Here, we review the current application of CRISPR-Cas9 and prime editing for SCD treatment and explore further opportunities to enhance prime editing.
References
GBD 2021 Sickle Cell Disease Collaborators (2023). Global, Regional, and National Prevalence and Mortality Burden of Sickle Cell Disease, 2000-2021: a Systematic Analysis from the Global Burden of Disease Study 2021. The Lancet. Haematology, 10(8), e585–e599. https://doi.org/10.1016/S2352-3026(23)00118-7
Kato, G. J., Piel, F. B., Reid, C. D., Gaston, M. H., Ohene-Frempong, K., Krishnamurti, L., Smith, W. R., Panepinto, J. A., Weatherall, D. J., Costa, F. F., & Vichinsky, E. P. (2018). Sickle Cell Disease. Nature Reviews. Disease Primers, 4, 18010. https://doi.org/10.1038/nrdp.2018.10
Jensen F. B. (2009). The Dual Roles of Red Blood Cells in Tissue Oxygen Delivery: Oxygen Carriers and Regulators of Local Blood Flow. The Journal of Experimental Biology, 212(Pt 21), 3387–3393. https://doi.org/10.1242/jeb.023697
Rab, M. A. E., van Oirschot, B. A., Bos, J., Merkx, T. H., van Wesel, A. C. W., Abdulmalik, O., Safo, M. K., Versluijs, B. A., Houwing, M. E., Cnossen, M. H., Riedl, J., Schutgens, R. E. G., Pasterkamp, G., Bartels, M., van Beers, E. J., & van Wijk, R. (2019). Rapid and Reproducible Characterization of Sickling During Automated Deoxygenation in Sickle Cell Disease Patients. American Journal of Hematology, 94(5), 575–584. https://doi.org/10.1002/ajh.25443
Elendu, C., Amaechi, D. C., Alakwe-Ojimba, C. E., Elendu, T. C., Elendu, R. C., Ayabazu, C. P., Aina, T. O., Aborisade, O., & Adenikinju, J. S. (2023). Understanding Sickle Cell Disease: Causes, Symptoms, and Treatment Options. Medicine, 102(38), e35237. https://doi.org/10.1097/MD.0000000000035237
Neumayr, L. D., Hoppe, C. C., & Brown, C. (2019). Sickle Cell Disease: Current Treatment and Emerging Therapies. The American Journal of Managed Care, 25(18 Suppl), S335–S343.
Kassim, A. A., & Sharma, D. (2017). Hematopoietic Stem Cell Transplantation for Sickle Cell Disease: The Changing Landscape. Hematology/Oncology and Stem Cell Therapy, 10(4), 259–266. https://doi.org/10.1016/j.hemonc.2017.05.008
Frangoul, H., Altshuler, D., Cappellini, M. D., Chen, Y. S., Domm, J., Eustace, B. K., Foell, J., de la Fuente, J., Grupp, S., Handgretinger, R., Ho, T. W., Kattamis, A., Kernytsky, A., Lekstrom-Himes, J., Li, A. M., Locatelli, F., Mapara, M. Y., de Montalembert, M., Rondelli, D., Sharma, A., … Corbacioglu, S. (2021). CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. The New England Journal of Medicine, 384(3), 252–260. https://doi.org/10.1056/NEJMoa2031054
Singh, A., Irfan, H., Fatima, E., Nazir, Z., Verma, A., & Akilimali, A. (2024). Revolutionary Breakthrough: FDA Approves CASGEVY, the First CRISPR/Cas9 Gene Therapy for Sickle Cell Disease. Annals of Medicine and Surgery (2012), 86(8), 4555–4559. https://doi.org/10.1097/MS9.0000000000002146
Steinberg, M. H., Chui, D. H., Dover, G. J., Sebastiani, P., & Alsultan, A. (2014). Fetal Hemoglobin in Sickle Cell Anemia: a Glass Half Full?. Blood, 123(4), 481–485. https://doi.org/10.1182/blood-2013-09-528067
Parums D. V. (2024). Editorial: First Regulatory Approvals for CRISPR-Cas9 Therapeutic Gene Editing for Sickle Cell Disease and Transfusion-Dependent β-Thalassemia. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, 30, e944204. https://doi.org/10.12659/MSM.944204
FDA Approves First Gene Therapies to Treat Patients with Sickle cell disease. (2023). U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease#:~:text=Casgevy%2C%20a%20cell%2Dbased%20gene,type%20of%20genome%20editing%20technol
Anzalone, A. V., Randolph, P. B., Davis, J. R., Sousa, A. A., Koblan, L. W., Levy, J. M., Chen, P. J., Wilson, C., Newby, G. A., Raguram, A., & Liu, D. R. (2019). Search-and-Replace Genome Editing without Double-Strand Breaks or Donor DNA. Nature, 576(7785), 149–157. https://doi.org/10.1038/s41586-019-1711-4
Scholefield, J., & Harrison, P. T. (2021). Prime Editing - an Update on the Field. Gene Therapy, 28(7-8), 396–401. https://doi.org/10.1038/s41434-021-00263-9
Jackson S. P. (2002). Sensing and Repairing DNA Double-Strand Breaks. Carcinogenesis, 23(5), 687–696. https://doi.org/10.1093/carcin/23.5.687
Zhao, Z., Shang, P., Mohanraju, P., & Geijsen, N. (2023). Prime Editing: Advances and Therapeutic Applications. Trends in Biotechnology, 41(8), 1000–1012. https://doi.org/10.1016/j.tibtech.2023.03.004
Li, C., Georgakopoulou, A., Newby, G. A., Chen, P. J., Everette, K. A., Paschoudi, K., Vlachaki, E., Gil, S., Anderson, A. K., Koob, T., Huang, L., Wang, H., Kiem, H. P., Liu, D. R., Yannaki, E., & Lieber, A. (2023). In Vivo HSC Prime Editing Rescues Sickle Cell Disease in a Mouse Model. Blood, 141(17), 2085–2099. https://doi.org/10.1182/blood.2022018252
Kim, D. Y., Moon, S. B., Ko, J. H., Kim, Y. S., & Kim, D. (2020). Unbiased Investigation of Specificities of Prime Editing Systems in Human Cells. Nucleic Acids Research, 48(18), 10576–10589. https://doi.org/10.1093/nar/gkaa764
Everette, K. A., Newby, G. A., Levine, R. M., Mayberry, K., Jang, Y., Mayuranathan, T., Nimmagadda, N., Dempsey, E., Li, Y., Bhoopalan, S. V., Liu, X., Davis, J. R., Nelson, A. T., Chen, P. J., Sousa, A. A., Cheng, Y., Tisdale, J. F., Weiss, M. J., Yen, J. S., & Liu, D. R. (2023). Ex Vivo Prime Editing of Patient Haematopoietic Stem Cells Rescues Sickle-Cell Disease Phenotypes After Engraftment in Mice. Nature Biomedical Engineering, 7(5), 616–628. https://doi.org/10.1038/s41551-023-01026-0
Hosseini, S. Y., Mallick, R., Mäkinen, P., & Ylä-Herttuala, S. (2024). Insights into Prime Editing Technology: A Deep Dive into Fundamentals, Potentials, and Challenges. Human Gene Therapy, 10.1089/hum.2024.043. Advance online publication. https://doi.org/10.1089/hum.2024.043
Jiang, L., & Yao, S. (2022). Enhancing Prime Editing Via Inhibition of Mismatch Repair Pathway. Molecular Biomedicine, 3(1), 7. https://doi.org/10.1186/s43556-022-00072-5
ClinicalTrials.gov. National Library of Medicine. https://clinicaltrials.gov/search?cond=Sickle%20Cell%20Disease&term=Sickle%20Cell%20Anemia&intr=gene%20therapy
Abraham, A. A., & Tisdale, J. F. (2021). Gene Therapy for Sickle Cell Disease: Moving from the Bench to the Bedside. Blood, 138(11), 932–941. https://doi.org/10.1182/blood.2019003776
Kanter, J., & Falcon, C. (2021). Gene Therapy for Sickle Cell Disease: Where We Are Now?. Hematology. American Society of Hematology. Education Program, 2021(1), 174–180. https://doi.org/10.1182/hematology.2021000250
Piel, F. B., Hay, S. I., Gupta, S., Weatherall, D. J., & Williams, T. N. (2013). Global Burden of Sickle Cell Anaemia in Children Under Five, 2010-2050: Modelling Based on Demographics, Excess Mortality, and Interventions. PLoS Medicine, 10(7), e1001484. https://doi.org/10.1371/journal.pmed.1001484
Esoh, K., Wonkam-Tingang, E., & Wonkam, A. (2021). Sickle Cell Disease in Sub-Saharan Africa: Transferable Strategies for Prevention and Care. The Lancet. Haematology, 8(10), e744–e755. https://doi.org/10.1016/S2352-3026(21)00191-5
Grosse, S. D., Odame, I., Atrash, H. K., Amendah, D. D., Piel, F. B., & Williams, T. N. (2011). Sickle Cell Disease in Africa: a Neglected Cause of Early Childhood Mortality. American Journal of Preventive Medicine, 41(6 Suppl 4), S398–S405. https://doi.org/10.1016/j.amepre.2011.09.013
Makani, J., Cox, S. E., Soka, D., Komba, A. N., Oruo, J., Mwamtemi, H., Magesa, P., Rwezaula, S., Meda, E., Mgaya, J., Lowe, B., Muturi, D., Roberts, D. J., Williams, T. N., Pallangyo, K., Kitundu, J., Fegan, G., Kirkham, F. J., Marsh, K., & Newton, C. R. (2011). Mortality in Sickle Cell Anemia in Africa: a Prospective Cohort Study in Tanzania. PloS One, 6(2), e14699. https://doi.org/10.1371/journal.pone.0014699
DeMartino, P., Haag, M. B., Hersh, A. R., Caughey, A. B., & Roth, J. A. (2021). A Budget Impact Analysis of Gene Therapy for Sickle Cell Disease: The Medicaid Perspective. JAMA Pediatrics, 175(6), 617–623. https://doi.org/10.1001/jamapediatrics.2020.7140
Li G. M. (2008). Mechanisms and Functions of DNA Mismatch Repair. Cell Research, 18(1), 85–98. https://doi.org/10.1038/cr.2007.115
Ferreira da Silva, J., Oliveira, G. P., Arasa-Verge, E. A., Kagiou, C., Moretton, A., Timelthaler, G., Jiricny, J., & Loizou, J. I. (2022). Prime Editing Efficiency and Fidelity Are Enhanced in the Absence of Mismatch Repair. Nature Communications, 13(1), 760. https://doi.org/10.1038/s41467-022-28442-1
Chen, P. J., Hussmann, J. A., Yan, J., Knipping, F., Ravisankar, P., Chen, P. F., Chen, C., Nelson, J. W., Newby, G. A., Sahin, M., Osborn, M. J., Weissman, J. S., Adamson, B., & Liu, D. R. (2021). Enhanced Prime Editing Systems by Manipulating Cellular Determinants of Editing Outcomes. Cell, 184(22), 5635–5652.e29. https://doi.org/10.1016/j.cell.2021.09.018
Mathis, N., Allam, A., Kissling, L., Marquart, K. F., Schmidheini, L., Solari, C., Balázs, Z., Krauthammer, M., & Schwank, G. (2023). Predicting Prime Editing Efficiency and Product Purity by Deep Learning. Nature Biotechnology, 41(8), 1151–1159. https://doi.org/10.1038/s41587-022-01613-7
Singh, A., Smedley, G. D., Rose, J. G., Fredriksen, K., Zhang, Y., Li, L., & Yuan, S. H. (2024). A High Efficiency Precision Genome Editing Method with CRISPR in iPSCs. Scientific Reports, 14(1), 9933. https://doi.org/10.1038/s41598-024-60766-4
Downloads
Posted
Categories
License
Copyright (c) 2024 Jiwon Jun
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.