Emerging Cell-Based Gene Therapies in Sickle Cell Disease: A Systematic Review of Casgevy and Lyfgenia

REVIEW
Zainab Fuad, Zainab A. Redha, Aqeela Abuidrees

 
For citation: Fuad Z, Redha ZA, Abuidrees A. Emerging Cell-Based Gene Therapies in Sickle Cell Disease: A Systematic Review of Casgevy and Lyfgenia. International Journal of Biomedicine. 2024;14(3):379-385. doi:10.21103/Article14(3)_RA2
 
Originally published September 6, 2024

Abstract: 

Background: In 2023, the FDA approved two emerging cell-based gene therapies for the treatment of severe sickle cell disease (SCD): Casgevy and Lyfgenia. Casgevy utilizes the newer CRISPR/Cas9 technology, while Lyfgenia relies on a Lentiviral vector. These therapies consist of autologous hematopoietic stem cell transplantation, in which the cells are genetically modified before infusing them back into the body.
The study aim was to conduct a thorough systematic review to determine an efficient choice between Casgevy and Lyfgenia by comparing their ability to increase anti-sickling hemoglobin and eliminate vaso-occlusive crises (VOCs), factoring in the adverse effects caused by each process.
Methods and Results: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines. Ten articles were analyzed and compared after searching PubMed and Google Scholar databases.
Both therapy strategies were equally efficient in eliminating VOC and had similar effects on anti-sickling hemoglobin fractions. Their adverse effects are also similar and are related to the chemotherapy shared between autologous and allogenic transplants and not the gene therapies themselves, barring the occurrence of acute myeloid leukemia in 2 patients receiving the unmodified version of Lyfgenia.
Conclusion: Casgevy and Lyfgenia are equally effective in their functions, although Casgevy appears to be the safer choice. However, the lack of follow-up for the patients in either gene therapy’s respective trials leads to a lack of confidence in firm declarations.

Keywords: 
sickle cell disease • CRISPR/Cas9 • exa-cel • lovo-cel
References: 
  1. Hoban MD, Orkin SH, Bauer DE. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood. 2016 Feb 18;127(7):839-48. doi: 10.1182/blood-2015-09-618587. Epub 2016 Jan 12. PMID: 26758916; PMCID: PMC4760089.
  2. Khemani K, Katoch D, Krishnamurti L. Curative Therapies for Sickle Cell Disease. Ochsner J. 2019 Summer;19(2):131-137. doi: 10.31486/toj.18.0044. PMID: 31258425; PMCID: PMC6584191.
  3. Saber W, Opie S, Rizzo JD, Zhang MJ, Horowitz MM, Schriber J. Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood. 2012 Apr 26;119(17):3908-16. doi: 10.1182/blood-2011-09-381699. Epub 2012 Feb 10. PMID: 22327226; PMCID: PMC3350357.
  4. Frangoul H, Altshuler D, Cappellini MD, Chen YS, Domm J, Eustace BK, Foell J, de la Fuente J, Grupp S, Handgretinger R, Ho TW, Kattamis A, Kernytsky A, Lekstrom-Himes J, Li AM, Locatelli F, Mapara MY, de Montalembert M, Rondelli D, Sharma A, Sheth S, Soni S, Steinberg MH, Wall D, Yen A, Corbacioglu S. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N Engl J Med. 2021 Jan 21;384(3):252-260. doi: 10.1056/NEJMoa2031054. Epub 2020 Dec 5. PMID: 33283989.
  5. Kanter J, Walters MC, Krishnamurti L, Mapara MY, Kwiatkowski JL, Rifkin-Zenenberg S, Aygun B, Kasow KA, Pierciey FJ Jr, Bonner M, Miller A, Zhang X, Lynch J, Kim D, Ribeil JA, Asmal M, Goyal S, Thompson AA, Tisdale JF. Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease. N Engl J Med. 2022 Feb 17;386(7):617-628. doi: 10.1056/NEJMoa2117175. Epub 2021 Dec 12. PMID: 34898139.
  6. Kanter J, Thompson AA, Pierciey FJ Jr, Hsieh M, Uchida N, Leboulch P, Schmidt M, Bonner M, Guo R, Miller A, Ribeil JA, Davidson D, Asmal M, Walters MC, Tisdale JF. Lovo-cel gene therapy for sickle cell disease: Treatment process evolution and outcomes in the initial groups of the HGB-206 study. Am J Hematol. 2023 Jan;98(1):11-22. doi: 10.1002/ajh.26741. Epub 2022 Oct 10. PMID: 36161320; PMCID: PMC10092845.
  7. Leonard A, Tisdale JF. A pause in gene therapy: Reflecting on the unique challenges of sickle cell disease. Mol Ther. 2021 Apr 7;29(4):1355-1356. doi: 10.1016/j.ymthe.2021.03.010. Epub 2021 Mar 19. PMID: 33743192; PMCID: PMC8058500.
  8. Frangoul H, Locatelli F, Sharma A, Bhatia M, Mapara M, Molinari L, Wall D, Liem RI, Telfer P, Shah AJ, Cavazzana M, Corbacioglu S, Rondelli D, Meisel R, Dedeken L, Lobitz S, de Montalembert M, Steinberg MH, Walters MC, Eckrich MJ, Imren S, Bower L, Simard C, Zhou W, Xuan F, Morrow PK, Hobbs WE, Grupp SA; CLIMB SCD-121 Study Group. Exagamglogene Autotemcel for Severe Sickle Cell Disease. N Engl J Med. 2024 May 9;390(18):1649-1662. doi: 10.1056/NEJMoa2309676. Epub 2024 Apr 24. PMID: 38661449.
  9. Hsieh MM, Bonner M, Pierciey FJ, Uchida N, Rottman J, Demopoulos 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. 2020 May 12;4(9):2058-2063. doi: 10.1182/bloodadvances.2019001330. PMID: 32396618; PMCID: PMC7218414.
  10. Goyal S, Tisdale J, Schmidt M, Kanter J, Jaroscak J, Whitney D, Bitter H, Gregory PD, Parsons G, Foos M, Yeri A, Gioia M, Voytek SB, Miller A, Lynch J, Colvin RA, Bonner M. Acute Myeloid Leukemia Case after Gene Therapy for Sickle Cell Disease. N Engl J Med. 2022 Jan 13;386(2):138-147. doi: 10.1056/NEJMoa2109167. Epub 2021 Dec 12. PMID: 34898140.
  11. Jones RJ, DeBaun MR. Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both, or neither. Blood. 2021 Sep 16;138(11):942-947. doi: 10.1182/blood.2021011488. PMID: 34115136.
  12. Kanter J, Falcon C. Gene therapy for sickle cell disease: where we are now? Hematology Am Soc Hematol Educ Program. 2021 Dec 10;2021(1):174-180. doi: 10.1182/hematology.2021000250. PMID: 34889358; PMCID: PMC8791177.
  13. Subica AM. CRISPR in Public Health: The Health Equity Implications and Role of Community in Gene-Editing Research and Applications. Am J Public Health. 2023 Aug;113(8):874-882. doi: 10.2105/AJPH.2023.307315. Epub 2023 May 18. PMID: 37200601; PMCID: PMC10323846.
  14. Rossi M. Acknowledging the Approval of World-First Gene Therapy for Sickle Cell Disease Through CRISPR-Mediated Gene Editing. Science Reviews - Biology. 2023;4(3):15-18. doi: 10.57098/SciRevs.Biology.2.4

Download Article
Received July 15, 2024.
Accepted August 28, 2024.
©2024 International Medical Research and Development Corporation.