The Food and Drug Administration on Friday approved a new therapy based on Crispr gene editing to treat sickle cell disease, marking the first time a treatment using the technology has secured a regulatory green light in the U.S. amid hopes the revolutionary tool will emerge from the lab and transform medicine.
The FDA authorized Crispr-based therapy Casgevy for the treatment of sickle cell disease in patients ages 12 years and older.
Casgevy, which is produced by Boston-based Vertex Pharmaceuticals and Switzerland’s Crispr Therapeutics and is also known as exagamglogene autotemcel, or exa-cel, is a first-of-its-kind treatment that uses the powerful gene-editing tool Crispr to target the underlying cause of sickle cell.
Sickle cell disease, also called sickle cell anemia, is a group of inherited blood disorders that affect the body’s ability to produce functioning haemoglobin, the protein in red blood cells responsible for carrying oxygen around the body.
The genetic mutation responsible for sickle cell disease means red blood cells fold, or sickle, where they can block blood vessels and prevent oxygen from being ferried around the body, triggering serious and potentially fatal problems like severe pain, stroke and organ damage.
Clinical trials of the therapy suggest Casgevy, which is given as a one-time treatment, can help relieve symptoms and offers hope of a cure for the condition that has largely eluded scientists beyond risky bone marrow transplants.
Approximately 100,000 people are estimated to have sickle cell disease across the U.S., most of whom are Black.
Casgevy, which edits DNA inside the human body, doesn’t actually fix the root cause of sickle cell disease. Rather than fixing the mutation responsible for faulty haemoglobin production, Casgevy targets genes responsible for producing a different kind of haemoglobin that is normally switched off shortly after birth. This genetic workaround triggers the production of typically inhibited fetal haemoglobin in the body, which helps blood cells keep their healthy, disc-like shape. While the treatment is administered once, the whole process can take months and includes laboratory work to modify blood cells and recovery in hospital after the modified cells are infused into patients.
The FDA’s decision comes weeks after Britain’s medical regulator gave exa-cel the green light, becoming the world’s first regulator to approve a Crispr-based therapy. At the time, Vertex CEO and President Reshma Kewalramani celebrated the approval as “a historic day in science and medicine.” Crispr’s journey to the clinic from its discovery and use in the lab has been a rapid one. The tool, derived from bacterial immune systems, was discovered little over a decade ago and scored its discoverers the 2020 Nobel Prize in Chemistry. By allowing scientists to manipulate DNA with precision—the tool is often described as a pair of genetic scissors—it was swiftly hailed as a tool of transformative potential across the life sciences, with potential applications ranging from transferring traits for things like disease resistance across species, editing faulty genes in medical practice or even resurrecting extinct animals. While there are clear benefits, experts warn the technology is a double-edged sword. For example, while Crispr could be used to make a virus benign to humans it could also be used to engineer a more virulent pathogen. The ability to tweak human DNA also raises the prospect of alterations designed to enhance rather than fix, a potential for a slippery slope towards eugenics.
What To Watch For
The U.K.’s medical regulator authorized Casgevy to treat beta thalassemia (β-thalassemia) as well as sickle cell disease. Beta thalassemia is another inherited blood disorder characterized by haemoglobin production. The FDA is also considering the therapy for beta thalassemia and is due to make a decision by the end of March next year.
What We Don’t Know
When considering the treatment, the FDA’s advisors—who endorsed the treatment—said they were confident of the drug’s efficacy and benefit but were wary of theoretical consequences of human genetic modifications. Given the novelty of the technology and its use in the clinic, experts warn there could be unintended outcomes of unknown consequence, for example if the therapy were to trigger genetic alterations elsewhere (called off-target alterations). The panel was clear, however, that the clear clinical benefit of the therapy should not be overshadowed by any theoretical concerns. The British regulator said it found no significant safety concerns and said Casgevy’s safety would be closely monitored following approval.
U.K. Greenlights World’s First Crispr Gene Editing Therapy (Forbes)