Introduction
Gene therapy has become a viable treatment option for hereditary blood illnesses, helping thousands worldwide. It is used to treat pyruvate kinase deficiency (absence of pyruvate kinase enzyme leading to breakdown of red blood cells), sickle cell disease (the presence of sickle-shaped red blood cells which eventually cause early death of red blood cells), and β-thalassemia (absence of β-globin necessary for hemoglobin to carry oxygen), among other inherited blood diseases.
Lentiviral vectors that incorporate a corrected form of the defective gene are used to repair hematopoietic stem cells. Although effective, this method is uncontrollable regarding natural regulation and gene integration. Gene editing is a more accurate and secure method of correcting these genes without affecting the remainder of the genome, especially using techniques like CRISPR/Cas9. Researchers are utilizing CRISPR/Cas9 systems and other forms of genome editing to treat hereditary blood disorders, including sickle cell disease and thalassemia.
They have had encouraging effects, such as resolving hemoglobin problems and activating specific beneficial chains in blood cells. Therapeutic genes have been effectively inserted according to the body's natural processes.
Gene editing for various blood disorders is progressing from early testing to demonstrating genuine promise in clinical trials, thanks to lessons learned from previous gene therapy initiatives. There is promise for future therapies for several genetic disorders, as effective treatments for β-thalassemia and sickle cell disease have already been provided to those affected.
What Is Gene Editing?
Gene editing, sometimes called genome editing, is the name given to a potent class of technologies that enable researchers to modify an organism's DNA at certain sites. This implies that individuals can alter, add, or delete genetic information, which may result in modifications to physical features, illness risk, and other attributes.
How Does Gene Editing Work?
Gene editing works in the following ways:
Targeting: Imagine DNA as a lengthy instruction manual with all the knowledge needed to create and maintain an organism. Gene editing instruments function as accurate molecular shears, capable of focusing on certain regions inside this guidebook.
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Editing: Several techniques may be employed to carry out the edit after the target area has been determined.
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Correction: Fixing mistakes or mutations in the DNA sequence that already exist.
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Removal: Cutting out undesirable or damaged DNA segments.
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Insertion: The introduction of novel, advantageous DNA sequences.
Cellular Repair: Following the edit, the DNA is replicated back together by the modifications made by the cell's repair systems.
What Are the Different Gene Editing Tools?
Gene editing has been made possible by several technologies, each with unique advantages and disadvantages.
Among the well-known instances are:
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CRISPR-Cas9: Currently the most widely used and adaptable technique, CRISPR-Cas9 targets and precisely cuts DNA using a bacterial immune system.
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Transcription Activator-Like Effector Nucleases, or TALENs: These proteins have been engineered to identify and cut certain DNA sequences.
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Zinc Finger Nucleases (ZFNs): These are proteins with modified DNA-binding domains designed to bind and edit certain regions of DNA.
Which Is the Most Common Gene Editing Tool For Blood Disorders and How Does it Work?
The most common and widely used gene editing tool for blood disorders is CRISPR-Cas9. The 2020 Nobel Prize winners who created CRISPR-Cas9 gene editing can accurately remove, add, or swap out specific DNA segments from a live cell.CRISPR gene-editing-based medicine (Casgevy) targets the BCL11A gene, which is involved in inhibiting the formation of fetal hemoglobin (HbF), using CRISPR-Cas9.
Hemoglobin type HbF is often exclusively seen in fetuses and neonates. Compared to adult hemoglobin, it has a stronger affinity for oxygen and can stop red blood cells from destroying or sickling. Individuals with naturally elevated HbF levels with sickle cell disease or beta thalassemia typically experience fewer severe symptoms and fewer consequences.
After a chemotherapy treatment that destroys the patient's remaining bone marrow, the patient's hematopoietic stem cells (the cells in the bone marrow that make new blood cells) are extracted and modified in a lab using CRISPR-Cas9. The patient is then infused with these modified stem cells back into the body. Subsequently, the altered stem cells replenish the bone marrow and generate red blood cells with elevated hemoglobin levels.
What Do Clinical Trials Results Show?
Studies by the UK Regulatory Agency for Medicines and Healthcare Products (MHRA) involving 42 patients with transfusion-dependent beta thalassemia and 29 individuals with sickle cell disease have been ongoing long enough to analyze therapy efficacy. The outcomes in both instances have been encouraging. They have all demonstrated drops in hemolysis (the breaking down of red blood cells) indicators and rises in HbF levels.
The most notable results were that 12 months after starting therapy, 97 percent of sickle cell disease patients no longer experienced vaso-occlusive crises (VOCs), and 93 percent of beta-thalassemia patients no longer required frequent blood transfusions. They frequently necessitate hospitalization and narcotic therapy (use of opioids to reduce pain), and they are the primary cause of morbidity and death in sickle cell patients.
Additionally, the therapy has been well tolerated, and there have been no significant side effects from the gene editing. Infections, low blood counts, and hair loss, all of which are believed to be transient and controllable, have been the most frequent adverse effects linked to chemotherapy treatment.
What Are the Advantages and Disadvantages of Gene Editing for Blood Disorders?
The following are the advantages and disadvantages of gene editing for blood disorders.
Advantages:
Apart from providing a one-time remedy for blood abnormalities, this approval could lead to further uses of CRISPR-Cas9 in treating hereditary illnesses. With its ability to be adapted to various targets and illnesses, CRISPR-Cas9 is a flexible and adaptable technology that is already transforming the medical industry.
Disadvantages:
But there are still a lot of difficulties to overcome. Because the processes for isolating, modifying, and returning hematopoietic stem cells into the bone marrow are well known, blood diseases are suitable candidates for this type of treatment. It is far more difficult to use gene editing methods on most other cell types safely.
Cost is another factor that may come up, and for less prevalent genetic diseases, the cost becomes increasingly exorbitant. Although the cost of Casgevy is unknown, sickle cell and beta thalassemia are also quite frequent conditions.
Conclusion
Precision therapy for blood diseases is entering a new age, with gene editing at its forefront. There is promise for more precise, effective therapies due to the possibility of directly addressing genetic abnormalities. The success and general acceptance of gene editing in changing the landscape of blood disease therapeutics will depend on finding the correct balance between scientific innovation, ethical considerations, and safety precautions as research advances.
