Introduction:
Casgevy is a trademark name for a novel gene therapy that uses CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia, two inherited blood disorders that affect millions of people worldwide. CRISPR-Cas9 is a powerful tool that can edit the DNA of living cells with high precision and efficiency. Casgevy aims to correct the genetic defect that causes these diseases by restoring the production of fetal hemoglobin, a form of hemoglobin that is normally present only in newborns and can prevent the harmful effects of sickle hemoglobin or β-globin deficiency.
What are Sickle Cell Disease and β-thalassemia?
Sickle cell disease and β-thalassemia are two inherited blood disorders that affect the production and function of hemoglobin, the protein that carries oxygen in red blood cells.
Cause of Sickle Cell Disease and β-thalassemia
Sickle cell disease and β-thalassemia are caused by mutations in the gene, which encodes the β-globin subunit of hemoglobin, the protein that carries oxygen in red blood cells.
In sickle-cell disease, body produces abnormal hemoglobin. It causes the shape and texture of blood cells to change, making them clump together and stick to the walls of blood vessels. These clumps block the flow of blood and reduce the amount of oxygen that reaches the tissues, which can trigger episodes of intense pain, called pain crises. Mutations in the case of β-thalassemia lead to low levels of hemoglobin and red blood cells in the blood, which can result in symptoms such as tiredness, breathlessness, and irregular heart rhythms.
Treatment options for Sickle Cell Disease and β-thalassemia
The current treatment options for these diseases are limited and often require lifelong blood transfusions and iron chelation therapy, which can have serious side effects and complications. The only curative option is allogeneic hematopoietic stem cell transplantation (HSCT), which involves replacing the patient’s bone marrow with healthy donor cells. However, this procedure is risky, costly, and dependent on the availability of a compatible donor, which is often scarce for patients of African or Asian descent.
However, this avenue can change now with the recent approval of Casgevy by UK authorities and, that is under scrutiny by the FDA in the US and EMA in Europe.
What is Casgevy?
Casgevy is First-ever approved CRISPR-based therapy. Casgevy is a CRISPR/Cas9 gene-editing tool that can correct the faulty that leads to Sickle Cell Disease and Beta-thalassemia. Casgevy uses the Crispr-Cas9 tool to edit the gene in blood stem cells that are taken from the bone marrow of patients. The CRISPR-Cas9 system consists of two components: a guide RNA that recognizes a specific DNA sequence and a Cas9 enzyme that cuts the DNA at that site. In this way, Casgevy makes corrections in the faulty gene that modified cells are then administered into patient’s body via Intravenous injection.
How Casgevy works?
Casgevy uses Cas9, a molecular scissors, to cut the DNA of a gene called BCL11A, which normally stops the production of fetal hemoglobin, a type of hemoglobin that is only made in fetuses. By breaking this gene, Casgevy allows the production of fetal hemoglobin, which does not have the same defects as adult hemoglobin in people with sickle-cell disease or β-thalassaemia.
Before the gene-edited cells are returned to the body, people need to undergo a treatment that prepares the bone marrow to accept the modified cells. Once given, the stem cells produce red blood cells containing fetal hemoglobin. This improves symptoms by increasing the oxygen delivery to tissues. Patients may need to stay in a hospital facility for at least a month while the treated cells settle in the bone marrow and start to make red blood cells with the stable form of hemoglobin.
Overview of Clinical Trials
The Casgevy made its way to successful approval after robust study and clinical trial. The study on sickle-cell disease included 45 people, and they have interim results for 29 participants. After treatment with Casgevy, 28 of them experienced complete relief from painful episodes for at least one year following the treatment.
They also tested Casgevy for a serious type of β-thalassemia. Usually, people with this condition get blood transfusions every month. In the study, Casgevy was tested on 54 patients. Out of them, 42 stayed in the study long enough to give early results. Among these 42, 39 didn’t need a blood transfusion for at least a year. The other three needed fewer blood transfusions, reduced by more than 70%.
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Side Effects and Safety of Casgevy
The safety and efficacy of Casgevy have been tested in two clinical trials, one for patients with TDT and the other for patients with SCD. The results of these trials have been published in the New England Journal of Medicine and Nature Medicine, respectively. The trials showed that Casgevy was able to increase the levels of fetal hemoglobin and reduce the need for blood transfusions in most patients. The trials also reported that Casgevy was well tolerated and did not cause any serious adverse events related to the gene therapy.
People in the ongoing trials experienced side effects such as nausea, fatigue, fever, and a higher risk of infection. However, there were no significant safety issues found. The MHRA (Medicines and Healthcare Products Regulatory Agency) and the company making the treatment are keeping a close eye on the safety of the technology and will share more results later.
Challenges and Limitations of Casgevy: Crispr-Cas9 Gene Editing for Sickle Cell Disease and β-thalassemia.
A notable concern surrounding the use of CRISPR–Cas9, the gene-editing tool employed in the ongoing trials, is the potential for unintended genetic modifications that may have unpredictable effects. David Rueda, a geneticist from Imperial College London, has highlighted the well-known fact that CRISPR technology while promising in its ability to precisely edit genes, can also introduce unintended alterations to the genetic code.
In order to address this concern and gain a more comprehensive understanding of the safety profile, Rueda emphasizes the importance of scrutinizing the complete gene//tic data of the cells subjected to the CRISPR–Cas9 treatment. Comprehensive analysis through whole-genome sequencing would provide insights into any inadvertent genetic changes that might have occurred during the gene-editing process.
However, in clinical trials, no unintended modifications have been observed in treated patients so far.
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Regulatory Status of Casgevy: Crispr-Cas9 Gene Editing for Sickle Cell Disease and β-thalassemia.
Casgevy is currently under review by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for approval as a treatment for sickle cell disease and β-thalassemia.
Conclusion
If approved, Casgevy would be the first gene therapy based on CRISPR-Cas9 to reach the market and could offer new hope for millions of patients suffering from these debilitating diseases.
