First US gene editing program using CRISPR for the treatment of genetic diseases

In an innovative experiment, a 34-year-old Mississippi mother and mother of four is in the spotlight for volunteering to be the subject of CRISPR's gene editing in the US. Hoping to find a cure for painful sickle cell disease which she has suffered all her life.

3D rendering, edition of Crispr's DNA. Image Credit: Nathan Devery / Shutterstock

Victoria Gray is a black housewife who was born with sickle cell disease, a blood disorder that affects approximately 100,000 Americans. This disease, which is much more common among blacks, is due to a single amino acid switch at a point in the DNA chain that encodes a molecule called hemoglobin. Hemoglobin carries oxygen to all body tissues and discharges there. The normal variant of hemoglobin, found in healthy people, is called HbA.

People with sickle cell disease have a variant called HbS, caused by the replacement of one amino acid by another at a given time. This seemingly minor error has devastating consequences on the nature of the molecule, which rapidly changes shape in an oxygen-poor environment, such as tissue. The red blood cells containing this defective hemoglobin thus become sickle-shaped or crescent-shaped and stick to each other. They are likely to form aggregates quickly within the smallest blood vessels supplying the tissues. This cuts the blood supply to the cells, causing the death of local cells and tissue damage. The patient experiences episodes of severe pain, tissue-related complications, severe anemia, and shortened life span.

The researchers are now using an experimental gene editing technology called CRISPR, able to cut the defective gene responsible for producing HbS and to plug the DNA hole with gene insertion. which codes for, another variant of hemoglobin called HbF, produced during fetal life and very shortly thereafter. They hope that the patient will produce sufficient amounts of this HbF to heal.

The problem is that no one yet knows if the tool can do this correction as accurately as necessary. The danger is that adjacent genes may be damaged during the process, leading to complications that may occur now or later, and that can not be predicted.

Gray thinks it's worth the risk. She says, "It's horrible. When you can not walk or raise a spoon to feed yourself, it becomes very difficult. "

She was talking about her bed at the Nashville, Tennessee hospital, where she had received billions of cells modified with the help of CRISPR. These cells were taken from his own bone marrow and made to produce HbF. Gray's own producers of red blood cells were first eliminated in the same way as during a bone marrow transplant, to avoid the production of more defective hemoglobin.

Researcher David Altshuler said, "It's exciting to see that we could be on the cusp of developing a very effective treatment for sickle cell patients."

Many experts, such as Dr. Haydar Frangoul, director of the pediatric hematology / oncology program at the Sarah Cannon Institute, who directs the treatment, are of the same mind: it's a big problem that many patients could benefit. Several other sites are recruiting patients for research in the United States, Canada and Europe, hoping to get 45 patients aged 18 to 35 in total.

Laurie Zoloth talks about the ethics of research: "It's an exciting time in medicine. CRISPR promises the ability to modify the human genome and start directly modifying genetic diseases. However, she hopes that this study and similar studies have been submitted first to external expert review by the panel selected by the National Institutes of Health. She is concerned that this technology may produce excellent results in laboratory animals and in culture, but has not yet been tested in humans. The effects are therefore completely unknown.

However, says Frangoul, scientists are aware of the experimental nature of research. They intend to proceed very slowly and carefully, consistently following the steps followed by the FDA (Food and Drug Administration) among other expert bodies. He says, "We are very cautious about how we conduct this test in a very systematic way to carefully monitor patients for any complications of treatment."

Gray says she knows the risks and possible delays in benefits for other patients. She insists that the main aspect of the trial, for her, is the hope that the disease is cured as soon as possible.

Scientists expect a delay of several months before seeing the first evidence that the modified cells have invaded the patient's body and produce hemoglobin at clinically useful levels. It will take even longer to see the effects in terms of improving health. And it takes years, with careful monitoring, to identify any complication, establish safety or health risks, and badess the life expectancy of benefits.

However, Gray and other patients, who saw their quality of life deteriorate, who suffered painful pains and injuries to the joints, heart and other organs, were willing to submit to this lengthy trial in the US. hope that their suffering would end one day. And not only so, they hope that the psychological trauma that their illness exerts on themselves and on their loved ones will be relieved if this treatment succeeds.

The only other long-term effective treatment for this disease is bone marrow transplantation, which is extremely painful and can even be fatal if the body is attacked by the transplanted cells during an immune response. Not to mention that most patients find it difficult or impossible to find a donor. Gray, however, planned to follow this therapy to relieve the burden of her illness on her young children, when she heard about the CRISPR trial and volunteered to have it. Not only does it use the patient's own cells, but it avoids the use of a donor and avoids any risk of immune attack in the patient.

Some patients have already been treated with CRISPR for cancer, mainly in China but at least two in the United States. Other genetic diseases are being considered for this technology. A patient with another blood disorder called thalbademia has already been treated in Germany with the help of CRISPR by the same company, CRISPR Therapeutics, which is sponsoring the ongoing study. The company is encouraged by the early signs that this previous treatment appears to have begun to work in the thalbademia patient, who has now been transfused for four months and whose tests show that the modified brewed cells have begun to function normally in the bones. . bone marrow.

Frangoul summarizes as follows: "It allows many patients to be treated and to modify their illness so that it is moderate." Gray offers his point of view: "To be able to wake up without suffering. To be with my children and to see them grow up. It means the world to me. "