Sickle Cell Disease (SCD) is a genetic disorder that causes the production of abnormally shaped red blood cells, which are rigid, sickle-shaped, and can block blood flow. This leads to severe pain (sickle cell crises), organ damage (including liver, heart, and spleen), and a reduced life expectancy. Treatments like blood transfusions, pain management, and bone marrow transplants can help, but they are not curatives. Gene therapy trials are part of a new wave of potential curative treatments. The FDA has approved two cell-based gene therapies for sickle cell disease (SCD): Casgevy and Lyfgenia, marking significant advancements in treatment options for patients with this debilitating and life-threatening condition.
Casgevy (Vertex Pharmaceuticals): Uses CRISPR/Cas9 technology to edit blood stem cells, increasing the production of fetal hemoglobin (HbF), which prevents red blood cell sickling.
Lyfgenia (Bluebird Bio): Uses a lentiviral vector to modify blood stem cells to produce HbAT87Q, a gene-therapy derived hemoglobin that mimics normal adult hemoglobin.
Casgevy is the first FDA-approved gene therapy for (SCD) using CRISPR/Cas9 technology. It is specifically developed for patients 12 years and older who suffer from recurrent vaso-occlusive crises (VOC). Casgevy’s safety and effectiveness were evaluated in an ongoing, single-arm, multi-center trial involving adult and adolescent patients with sickle cell disease. The study included patients who had a history of at least two severe VOC episodes in the two years prior to screening, which are hallmark events in SCD. The trial primarily measured freedom from severe VOCs for at least 12 consecutive months during a 24-month follow-up period after receiving Casgevy. Of the 31 patients who had sufficient follow-up data, 29 patients (93.5%) achieved this outcome. This is a significant reduction in VOC episodes, demonstrating the effectiveness of Casgevy in alleviating one of the most debilitating aspects of SCD. All treated patients experienced successful engraftment of the edited blood stem cells, meaning that the modified cells attached to and proliferated within the bone marrow. Importantly, there were no cases of graft failure or graft rejection, a critical outcome in stem cell-based therapies. The therapy increased production of fetal hemoglobin (HbF), which is crucial for preventing red blood cell sickling. HbF is normally produced in fetuses but typically decreases after birth. Casgevy helps reactivate HbF production, which helps to reduce sickling and improve oxygen delivery in SCD patients. The safety profile of Casgevy was also closely monitored throughout the trial. The most common side effects reported are primarily related to the conditioning regimen (chemotherapy) required before the stem cell infusion:
- Low platelets (thrombocytopenia) and white blood cells (leukopenia)
- Mouth sores (mucositis), nausea, musculoskeletal pain, and abdominal pain.
- Febrile neutropenia (fever with low white blood cell count), a side effect commonly seen after chemotherapy.
- Headache and itching.
These side effects are expected due to the myeloablative conditioning (high-dose chemotherapy) used to prepare the patients for the infusion of the modified stem cells. No serious, life-threatening side effects have been observed, and all patients have been able to recover from the treatment-related adverse events. Patients treated with Casgevy will be followed in a long-term study to assess the safety and effectiveness of the therapy over time. This extended monitoring will help to ensure that any potential delayed side effects or long-term benefits are fully understood.
Image: Treatment Mechanism of Sickle Cell Disease; Key Players in the Therapeutic Market; Global Sickle Cell Disease Market Size
According to Data Bridge Market Research, “…Global Sickle Cell Disease Market size in 2023 is USD 2.79 billion. The market share is projected to grow at a CAGR of 13.21% and reach USD 7.52 billion by 2031….”.
Dr. Malini Gupta, Ph.D.
Sources
- https://rarediseases.org/rare-diseases/sickle-cell-disease/
- https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-authorization-first
- https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-fda-approval-lyfgeniatm-lovotibeglogene
- https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
- https://www.databridgemarketresearch.com/reports/global-sickle-cell-disease-market?srsltid=AfmBOorpV_FDI8B06vWBWa8HbStRj0LZXXA0dZcfuw4WLr3pLdOESg6G
- https://pmc.ncbi.nlm.nih.gov/articles/PMC8049447/#:~:text=The%20RNP%20(ribonecleoprotein)%20complex%20of,to%20reverse%20the%20disease%20phenotype.
- Figure elements – https://cen.acs.org/articles/94/i41/CRISPR-edits-sickle-cell-mutation.html
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