By: Rohith Karthik, Global and Public Health Sciences, 2027
Sickle cell anemia, also known as SS, is among the most prevalent groups of inherited disorders, casting a long and ominous shadow over individuals and communities worldwide. Its capacity to deform red blood cells and impair oxygen transport often leads to painful symptoms in patients, including swelling of the hands and feet, vision issues, and frequent infections [1]. Blood transfusions and medication are the current treatments in use. However, in December 2023, the U.S. Food and Drug Administration approved a set of new treatments that have the potential to revolutionize the way sickle cell anemia is treated.
One such treatment, Casgevy, represents the first cell-based gene therapy for the treatment of sickle cell disease (SCD) in patients 12 years and older. Additionally, one of these therapies, Casgevy stands as the first FDA-approved treatment employing CRISPR/Cas9, a form of genome editing technology. The groundbreaking procedure involves the modification of patients' hematopoietic (blood) stem cells through genome editing with CRISPR/Cas9 technology [2]. A total of 44 patients were treated with Casgevy. Of the 31 patients with sufficient follow-up time to be evaluable, 29 (93.5%) achieved significant improvement in their symptoms due to sickle cell anemia.
CRISPR, or clustered regularly interspaced palindromic repeats, are specific sequences found in the bacterial genome that provide defense against invading viruses when coupled with a set of CRISPR-associated (Cas) proteins. Among these associated proteins, Cas9, an endonuclease, cuts both strands of DNA. Cas9, targeting its intended site, is facilitated by a segment of RNA, which can be synthesized as a single strand known as synthetic single guide RNA (sgRNA). The RNA portion binding to the genomic DNA consists of 18–20 nucleotides. For the cutting process to occur, a particular DNA sequence of 2 to 5 nucleotides (the exact sequence dependent on the Cas9-producing bacteria) must be present at the 3’ end of the guide RNA; this is referred to as the protospacer adjacent motif (PAM). Subsequent to the DNA cut, repair can take place through two pathways: non-homologous end joining, resulting in random insertion/deletion of DNA, or homology-directed repair, where a homologous piece of DNA serves as a repair template [3]. The latter pathway enables precise genome editing, allowing for the delivery of the Cas9 nuclease and sgRNA along with the homologous DNA section containing the desired sequence alteration. This theoretically permits changes as precise as a single base-pair.
CRISPR/Cas9 can be directed to cut out the sequence of the DNA where the sickle cell mutation exists and then the modified blood stem cell is transplanted back into the patients. The cells can then attach and multiply in the bone marrow and increase the level of fetal hemoglobin (HbF), which facilitates oxygen delivery and thus prevents the sickling of red blood cells [4]. This treatment is a one-time use therapy that is specially made for each patient using their own stem cells, and so far no side effects have been observed, although additional trials should be conducted in a larger sample size [5].
The landscape of sickle cell anemia treatment has undergone a profound transformation in recent years, offering renewed hope to millions of individuals who battle this disease. The journey from simple pain medications to the current era of precision medicine and groundbreaking innovations has been nothing short of miraculous, and Casgevy is the most recent advancement that has the potential to alter the gene editing field.
References
“Sickle Cell Anemia - Symptoms and Causes.” Mayo Clinic, www.mayoclinic.org/diseases-conditions/sickle-cell-anemia/symptoms-causes/syc-20355876#.
FDA. “FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease.” FDA, 8 Dec. 2023, www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease.
Redman, Melody, et al. “What Is CRISPR/Cas9?” Archives of Disease in Childhood - Education & Practice Edition, vol. 101, no. 4, 8 Apr. 2016, pp. 213–215, https://doi.org/10.1136/archdischild-2016-310459.
Reardon, Sara. “FDA Approves First CRISPR Gene Editing Treatment for Sickle Cell Disease.” Scientific American, 8 Dec. 2023, www.scientificamerican.com/article/fda-approves-first-crispr-gene-editing-treatment-for-sickle-cell-disease/.
“Vertex Announces US FDA Approval of CASGEVYTM (Exagamglogene Autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia | Vertex Pharmaceuticals.” Vertex Pharmaceuticals, 2024, investors.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene.
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