Casgevy: Key Insights Into the First-Ever CRISPR Gene-Editing Therapy Approved for Sickle Cell Disease

The U.S. Food and Drug Administration (FDA) approved gene therapies targeting sickle cell disease, including the groundbreaking CRISPR treatment, Casgevy, by Vertex Pharmaceuticals and CRISPR Therapeutics. Approved by the UK MHRA last month, Casgevy marks a historic moment in gene therapy, raising concerns about affordability and long-term safety.

Sickle Cell Disease Treatment Using CRISPR Gene-Editing Therapy Approved

Sickle cell disease is an inherited blood disorder impacting approximately 100,000 Americans, which results in distorted red blood cells that become lodged in blood vessels, impeding blood flow and triggering painful episodes known as pain crises.

Regulatory approval has been granted for Bluebird Bio's lovo-cel (marketed as Lyfgenia), utilizing a distinct technology to replace the faulty gene responsible for sickle cell formation.

This marks a historic milestone in biotechnologies, particularly for CRISPR gene-editing, the groundbreaking technology that earned scientists Jennifer Doudna and Emmanuelle Charpentier the 2020 Nobel Prize in Chemistry as its pioneers.

This versatile technology is undergoing trials for various global human afflictions, spanning HIV, heart disease, cancer, and applications in agriculture and livestock. The approval signifies a significant scientific leap about a decade after the discovery of CRISPR technology, delivering the treatment to the potentially tens of thousands who could benefit may pose challenges.

How Does It Work?

Casgevy uses the CRISPR gene-editing technique, employing an enzyme known as Cas9 to excise genes from DNA. Functioning as "molecular scissors," Cas9 is directed to target DNA by a guiding RNA molecule, a mechanism inspired by the natural defense strategy of bacteria and archaea against viruses.

Specifically, Casgevy focuses on editing the BCL11A gene, responsible for encoding a protein that typically regulates the transition from fetal to adult hemoglobin shortly after birth. In individuals with sickle cell disease (SCD) and beta-thalassemia, the adult hemoglobin is defective.

Casgevy's objective is to disable BCL11A, allowing the body to continue producing fetal hemoglobin, as the adult version is ineffective. This involves extracting blood-making stem cells from the patient's bone marrow, editing the BCL11A gene using Casgevy in the laboratory, and then reintroducing the modified cells into the patient's body.

Before the infusion, patients must undergo chemotherapy with the drug busulfan to eliminate unedited cells in their bone marrow. The adjustment to the edited cells is a prolonged process, with patients potentially spending at least a month in a hospital facility as the modified cells establish themselves in the bone marrow and commence the production of red blood cells with stable hemoglobin.

In two late-stage clinical trials, Casgevy demonstrated success by restoring hemoglobin production and alleviating symptoms in most patients with SCD and beta-thalassemia. Among those with SCD, 28 out of 29 patients remained free of severe pain crises for at least a year after Casgevy treatment.

Similarly, 39 out of 42 beta-thalassemia patients did not require red blood cell transfusions during the same post-treatment period, with the remaining three patients being significantly less likely to need transfusions.

Is It Safe?

Casgevy's late-stage clinical trials showed no serious safety concerns, with reported transient side effects like fever and fatigue. Ongoing monitoring by regulatory bodies and the manufacturers, Vertex Pharmaceuticals and CRISPR Therapeutics, continues to assess the therapy's long-term safety.

However, general concerns persist about the safety of CRISPR-based therapies, particularly regarding "off-target" effects, where unintended genetic modifications may lead to unwanted side effects.

David Rueda, a Molecular and Cellular Biophysics chair at Imperial College London, emphasizes the importance of scrutinizing whole-genome sequencing data to identify any potential off-target effects in Casgevy-edited cells.