CRISPR-Cas9 Gene Editing on SCD - Zohaib Hussain '27

A New Approach to Treating Sickle Cell Disease: CRISPR-Cas9 Genome Editing

Sickle Cell Disease (SCD) is an inherited blood disorder that affects millions of people worldwide. Along with other blood disorders such as Beta Thalassemia, SCD is difficult to treat, let alone cure. Since the disorder is found within the DNA of the patient, the patient will always live with it unless their genome is altered.
SCD is caused by a single mutation in the HBB gene that codes for hemoglobin, a protein responsible for transporting oxygen in red blood cells. By mutating the gene, the disorder causes hematopoietic stem cells, cells that form red blood cells, to create destructured red blood cells. Whereas healthy red blood cells are circular and plump, red blood cells affected by SCD have a “sickled” appearance, similar to that of a crescent. The irregular shape restricts red blood cells from carrying and transporting oxygen throughout the body, leading to affected individuals experiencing delayed growth and development, anemia, organ damage, and vaso-occlusive crises – painful episodes where blood vessels get clogged by sickled red blood cells, forcing the body to shut down.
Even with extensive care, many patients with SCD are unable to be fully treated due to the high cost of traditional treatments, such as hematopoietic stem cell transplantation (HSCT). Therapies such as HSCT can be effective in temporarily mitigating the effects of SCD; however, only 18% of patients with SCD are eligible for HSCT since healthy stem cells can only be received by an HLA-matched donor – someone whose antigens are the same as the recipient’s. An unmatched donor that gives a patient their stem cells risks giving the recipient graft-versus-host disease (GVHD), a possible side effect where the donor’s transplanted immune cells attack the recipient’s body, causing organ damage, rashes, vomiting, and diarrhea. Along with many more side effects, the risk of GVHD makes HSCT worse than no treatment at all. Even if a patient matches with a donor, the patient must consider side effects such as infertility.
To find more effective treatments, scientists started looking into novel approaches, such as gene editing, that can be created to align with the specific needs of each patient; CRISPR-Cas9 is one genome editor that has been recently discovered to manipulate DNA. To make edits, genome engineers introduce a guide RNA (gRNA) that identifies a specific place in the genome to a Cas9 protein, which searches for and “cuts” the identified gene. Once a gene is cut, the DNA goes through a process called non-homologous end joining (NHEJ) to repair itself. The gene will introduce new DNA bases into its sequence until it fixes itself, resulting in a new, permanent edit.
The use of a CRISPR-Cas9 gene editing-based therapy for SCD had been approved by the FDA on December 8, 2023. Exaglamgogene autotemcel, named Casgevy, the gene therapy is performed by taking a collection of the patient’s blood stem cells and editing the mutation with CRISPR-Cas9. Once its mutation is fixed, the edited stem cells are put back into the patient to multiply. With many patients, Casgevy significantly reduces the amount of transfusions needed for a patient with SCD, as well as symptoms of the disorder.
Casgevy is a novel approach to curing SCD that may help with curing patients; however, the therapy doesn’t come without complications. Compared to traditional HSCT, which costs around $400,000, Casgevy can cost up to $2.2 million without hospital fees, extra medical care, or financial assistance. While some patients with SCD can benefit from having a one-time treatment, many patients may not be able to afford such treatment upfront and may have to receive financial aid or take out loans to pay for the therapy.
Anyone considering taking Casgevy should also consider the implications CRISPR-Cas9 gene editing has on humans; gene editing has long been a controversial topic amongst scientists who argue that editing the human genome, which has been passed down several generations, is unethical and dangerous due to the risk of off-target edits by genome editors. While Casgevy has been specifically engineered to avoid off-target edits to DNA, the risk for such mistakes is not impossible, just like with any genome editor. Even if doctors catch an off-target edit, fixing the mistake may add to the original cost of the treatment.
While Casgevy has side effects, patients and doctors should still consider that the therapy is still relatively new and will decrease in cost as resources become more readily available. Even if the price is currently expensive, genome engineers are researching ways to reduce costs, such as by editing cells inside the patient’s body without having to perform a transplant (known as in vivo editing). Methods like in vivo editing can make treatments more efficient and accessible, thereby bringing the price down and providing people with the care they need.
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