Victoria Gray should have died at 40. This is the life expectancy given to patients with sickle cell anemia, a malformation in a gene that makes red blood cells deformed and dysfunctional. It affects 300,000 births each year worldwide and causes unbearable pain. The young American, 37, cries when she thinks about it. It’s hard to forget the repeated transfusions, the increased risks of stroke, a life under the knife.
Then the “miracle” happened. In June 2019, scientists offered to test a promising innovation on her. We then talk to her about these “genetic scissors”, a biological revolution which is agitating specialists: molecules which, by cutting her DNA in the right place, could rid her of her bad blood. The treatment is risky, but if that’s all it is, you might as well accept it. From condemned, she is now cured.
Victoria Gray is the very first patient to have participated in clinical trials of this innovative treatment. Called Casgevy and developed by the American laboratory Vertex Pharmaceuticals, it has since been approved in the United Kingdom and the United States. Europe announced its marketing authorization on Friday, December 15. This is the very first medical application of Crispr-Cas9, this genome editing technique discovered by Emmanuelle Charpentier and Jennifer Doudna in 2012, who have since been awarded a Nobel Prize.
Foundation stone of the Crispr revolution
If around thirty gene therapies already exist, Crispr-Cas9, more malleable, easy and quick to use, was very early on expected to revolutionize the sector. It took only eleven years to convert bench-top innovation to which we already owe immense progress in fundamental research into a therapeutic upheaval. “Usually, for a new class of drug, you need thirty,” comments Serge Braun, scientific director of the AFM-Téléthon.
The authorization of a first treatment opens the way to a multitude of hopes, for all kinds of pathologies. “Casgevy could mark the transition of Crispr gene therapies into a mass era. A new medicine, centered around the genome, is taking hold,” rejoices Anne Galy, research director at Inserm and specialist in these techniques. Ultimately, researchers could cut the genome as they wish, to correct errors, and combat pathologies as varied as cancer, neurodegenerative diseases or HIV infection.
But if the first stone has been laid, there is still a long way to go before this technology really takes off. “This first treatment is a magnificent piece of work, but it is unlikely that the version of Crispr used will lead directly to many other medical applications outside of very similar situations, because it only allows one gene to be inactivated. As is, it is not optimized to correct or provide a gene, both in terms of effectiveness and safety”, analyzes Professor Alain Fischer, pioneer of gene therapies and founder of the Imagine Institute of Genetic Diseases.
A technique that is still imprecise
The Crispr model used by Vertex Pharmaceuticals cuts both strands of DNA at the gene that inhibits the fetal blood system. Carried out on cells from the spinal cord removed and then re-implanted, the operation orders the body to once again produce this primary blood, free from sickle cell disease. However, it is possible that unintentional cuts take place, or that repairs carried out by the body fail. Although these errors appear rare based on the data provided by the manufacturer, they will require close monitoring of patients for at least fifteen years.
On November 12, when the United Kingdom authorized treatment for sickle cell disease, three patients who benefited from basic editinga more precise version of the genetic scissors, were presented at the congress ofAmerican Heart Association in Philadelphia, in the USA. They suffered from high cholesterol, due to another genetic mutation. Thanks to the experimental operation, a simple injection this time, their liver was able to better regulate fat, avoiding complications.
Unlike previous versions of Crispr, the basic editing only cuts one strand of DNA and not both, which reduces the risk of errors. Discovered by David Liu, Harvard researcher and new hero of Crispr technologies, the device still needs to be improved and secured. According to Verve, the company that develops it, a patient who had not declared certain history saw his heart stop and then start again because of this experimental treatment, casting doubt on the toxicity of the process.
A booming area
Prolific, David Liu had also demonstrated a little earlier, in March 2023, that the basic editing could be used against spinal muscular atrophy, one of the genetic diseases that kills the most young children, because it blocks the development and use of muscles. A single injection is enough in mice. In August, another team showed that it was possible to improve, in the laboratory at least, the effectiveness of certain treatments against cancer, Car-T immunotherapies. Healthy cells are no longer targeted by the therapy, which previously caused serious side reactions.
Treatments based on the technique of basic editing could arrive shortly. And already, new versions of Crispr, allowing even cleaner inserts into the genome, are being studied. “David Liu also developed the prime editing, which allows you to remove or add a small DNA sequence, and the paste editing or the use of transposons to modify even longer pieces. For the moment, this is only pre-clinical work, but it is very promising,” rejoices Professor Fischer.
A real plus compared to current gene therapies
If these technologies are eagerly awaited, it is because they present real advantages compared to current gene therapies. Today, to treat a disease linked to a mutated gene, scientists bring an additional corrective gene into cells. But these genes are expressed continuously, whereas often, in our body, gene expression is not continuous. By directly correcting mutated genes using Crispr, specialists believe they can restore the normal functioning of cells. This should make it possible to treat a much larger number of pathologies.
It will also be necessary to manage not only to treat cells taken from patients and then reinjected, but also to manage to use Crispr-Cas9 directly in the body, through simple injections. “But this still poses significant challenges. In particular, we will have to find how to ensure that no germ cell is modified, so as not to cause hereditary mutations,” continues Anne Galy. Research is underway to find how to route and guide the chemical systems that cut the genome in the body, into which “vehicle” to slip these proteins, called “Cas9” to be effective, and reduce toxicity. A solution could come from small fat balls developed to deliver messenger RNA vaccines into our bodies.
Cost, the last obstacle
But to treat the sick, the biggest challenge will certainly be… economic. The sickle cell treatment received by Victoria Gray and the 70 other members of her clinical trial is sold for more than $2.2 million per patient in the United States. Such an amount limits the beneficiaries to patients born in countries capable of such reimbursements and to the wealthiest, while sickle cell disease is, for example, more widespread in Africa than elsewhere.
Last March, the Royal Society, the main British learned society, called for a “global commitment to affordable and equitable access to these treatments, as a matter of urgency”, on the sidelines of the most important summit on the issue, the International Summit on Human Genome Editing. “We are entering a second phase of the revolution induced by Crispr, much denser and broader, but we will have to find how to lower the costs of these new treatments, because they are not sustainable for the moment,” warns Marina Cavazzana, expert in gene therapies at the Necker-Enfants Malades hospital. No money, no revolution.
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