The revolutionary CRISPR gene editing was presented this Tuesday to the requested review of the US Drug Agency (FDA). After a seven-hour hearing, the health regulator seems closer to approving a treatment based on this technique and named exa-cel.
Permission was requested by laboratories Vertex Pharmaceuticals, based in Boston, and the Swiss CRISPR Therapeutics, whose stock trading was suspended for the duration of the session. Together they designed a therapy based on genome editing against a blood disorder: sickle cell anemia, a genetic malformation responsible for the transformation of red blood cells. It is one of the most frequent in the world, and affects millions of people, 100,000 in the United States alone. It also promises to improve the outlook of patients with another congenital anemia: beta-thalassemia, which requires lifelong transfusions.
Sickle cell anemia causes red blood cells, instead of the usual round shape, to acquire the silhouette of a half-moon, which causes them to hit the blood vessels and cause pain that is not consistent with -progress to a normal life. Most patients do not live beyond 40 or 50 years.
External experts summoned by the FDA offered to hear not so much the effectiveness or safety of exa-cel, but whether the methods used by Vertex and CRISPR Therapeutics, which have been shown to be successful in 29 out of 30 patients treated, there is the potential risk of making unwanted changes in DNA. This is what is known as “off-target editing”: genetic modifications that can be harmless or harmful if they affect certain regions of the genome. As it became clear this Tuesday, it is a priority for the US health regulator to guarantee that the treatment does not have these unexpected side effects.
At the end of the day, experts agree on the usefulness of further testing, but many of them express enthusiasm, as well as the belief that the benefits of exa-cel outweigh any doubts about its risks. Those responsible for Vertex plan to follow up the treated patients for the next 15 years to determine possible side effects.
What was not mentioned in the FDA meeting was one of exa-cel’s main obstacles: its price. It is expected to cost millions of dollars, which is almost impossible to manage in less developed countries, where the incidence of the disease is highest. “This is a disease that affects people of African, Southeast Asian and Mediterranean (Middle Eastern) descent,” explains hepatologist Karl Kassamon.
Tuesday’s process typically represents the final step before the agency makes a decision. The FDA has a December 8 deadline.
stories of pain
During the presentation, a dozen patients who have already benefited from the preliminary clinical trials shared their cases, with the request that the FDA give the green light to exa-cel (easier said than done its full name: “exagamglogene autotemcel”).
They describe unimaginable sufferings. Perhaps the most famous case is that of Victoria Gray, a black woman who was the first to undergo treatment and opened a public hearing on Tuesday to say that she consumed “three different opiates” to treat his pain and that During the worst crisis of his life, he remained awake for “three days.” “I can’t use my legs or arms; “I can’t even hold a fork to feed myself, nor wash my face.” Now, thanks to exa-cel, which he received in an experimental trial in Nashville, he can work full time, “contribute to the family economy” and dedicate himself “to his children,” and he gave up “blood transfusions, opiates and frequent hospitalizations.”
Another witness, Kelly Howard – also African American – recalled that before he was a year old he was hospitalized “more than 13 times” and that in 2022 the visits increased to 100. “The treatment I asked you which is approved for all anemia warriors Sickle cell saved me from the disease that I have been fighting for 33 years of my life,” he added.
What the doctors did to Gray and Howard was to take blood stem cells from their bone marrow, and send them to the laboratory where they were edited using the CRISPR-Cas9 technique. From the DNA, they cut a gene called BCL11A that controls the production of a protein, fetal hemoglobin, which is responsible for congenital anemia. The edited cells are frozen and sent back to the hospital, where, after chemotherapy treatment to kill the diseased blood cells in the brain, they are transplanted back into the patient. In a few weeks, the blood, which regenerates itself, is thus clean.
Once exa-cel is approved in the United States, Europe is expected to follow the same path.
In 2012, Jennifer Doudna and Emmanuelle Charpentier developed a method for high-precision genome editing that they named CRISPR-Cas9. That discovery, which is like a very sophisticated pair of genetic scissors, won them a Nobel Prize in Chemistry in 2020. The Swedish Academy immediately highlighted the possibilities of CRISPR to create new therapies against cancer or many others other inherited diseases, such as sickle cell anemia. or beta-thalassemia.
The agri-food industry is also rubbing its hands in the world of the possibilities that this new technique opens up.
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