First ever American gene-editing treatment using CRISPR for genetic disease

By Dr. Liji Thomas, MDJul 30 2019

In a pathbreaking experiment, a 34-year-old mother of four from Mississippi is in the limelight for volunteering to be the subject of CRISPR-mediated gene editing in the hope of achieving a cure for the painful sickle cell anemia with which she has suffered all her life.

3D Rendering Crispr DNA Editing. Image Credit: Nathan Devery / Shutterstock

Victoria Gray is a black stay-at-home mom, who was born with sickle cell anemia, a blood disorder that affects about 100,000 Americans. This disease, which is much more common among black people, is due to a single switch of amino acid at one point in the part of the DNA chain which codes for a molecule called hemoglobin. Hemoglobin carries oxygen to all the bodys tissues and unloads it there. The normal variant of hemoglobin, present in healthy people, is called HbA.

People with sickle cell anemia have a variant called HbS, caused by one amino acid being replaced by another at one point. This seemingly minor mistake has devastating consequences on the nature of the molecule, which changes shape rapidly in a low-oxygen environment, such as the tissues. This causes the red cells containing this defective hemoglobin to become sickle-shaped or crescentic, and to stick together. They are liable to rapidly form aggregates within the smaller blood vessels supplying the tissues. This cuts off blood supply to the cells there, causing local cell death and tissue damage. The patient experiences bouts of severe pain, tissue-related complications, severe anemia, and a shortened life span.

Now researchers are making use of an experimental gene-editing technology called CRISPR which can cut out the defective gene causing the production of HbS and patch the DNA hole with the insertion of the gene that codes for, yet another hemoglobin variant called HbF, produced during fetal life and a very short time thereafter. They hope that this will result in the patient producing sufficient amounts of this HbF for a cure.

The problem is that nobody knows yet whether the tool can accomplish this patching as precisely as required. The danger is present that adjacent genes may be damaged in the process, causing complications which may manifest now or later, and which cannot be predicted.

Gray thinks it’s worth the risk. She says, “It’s horrible. When you can’t walk or lift up a spoon to feed yourself, it gets real hard.”

She was speaking from her bed in the Nashville, Tennessee, hospital, where she had received billions of cells that had been modified using CRISPR. These cells were taken from her own bone marrow and engineered to produce HbF..Gray’s own red cell producers were first wiped out in the same way as during a bone marrow transplant, to ensure that no more of the defective hemoglobin was produced.

Researcher David Altshuler says, “It’s exciting to see that we might be on the cusp of a highly effective therapy for patients with sickle cell.”

Many experts like Dr Haydar Frangoul, director of the pediatric hematology/oncology program at the Sarah Cannon Institute which is conducting the treatment, agree, calling it a big deal which could benefit many patients. Several other sites are recruiting patients for the research in the US, Canada and Europe, hoping to get 45 patients between 18 and 35 years in total.

Laurie Zoloth addresses the ethics of the research: “This is an exciting moment in medicine. CRISPR promises the capacity to alter the human genome and to begin to directly alter genetic diseases.” However, she wishes that this and similar studies had been subjected first to external expert scrutiny by the panel selected by the National Institutes of Health. Her worry is that this technology has been demonstrated to produce great results in experimental animals and in culture, but it has not been tried in humans before. The effects are therefore completely unknown.

However, Frangoul says, the experimental nature of the research is kept in mind by the scientists who intend to proceed very slowly and carefully, keeping the steps under constant review by the US Food and Drug Administration (FDA) among other expert bodies. He says, “We are very cautious about how we do this trial in a very systematic way to monitor the patients carefully for any complications related to the therapy.”

Gray says she knows about the risks, and the possible delay in benefits for other patients. She insists that the chief aspect of the trial, for her, is the hope it gives that the disease will be cured sooner rather than later.

The scientists expect a delay of months before they see the first evidence that the modified cells have taken to the patient’s body and are producing the hemoglobin at clinically useful levels. It will require still more time to see the effects in terms of improved health. And years must elapse, with careful monitoring, to capture any complications, establish the safety or health risks, and to assess how long the benefits will last.

However, Gray and other patients, who have seen their life quality deteriorate, suffered agonies of pain, and experienced damage to their joints, heart and other organs, are ready to undergo this long trial in the hope that their suffering will end one day. And not only so, they hope that the psychological trauma their disease exerts on themselves and on their loved ones will be relieved if this treatment is found to succeed.

The only other successful long-term treatment for this condition is bone marrow transplant, which is extremely painful, and could even be fatal if the body is attacked by the transplanted cells in an immune reaction. Not to mention that most patients find it difficult or impossible to fnd a donor. Gray was considering undergoing this therapy, nonetheless, to relieve the load imposed by her disease on her young children, when she heard about the CRISPR trial and volunteered for it. Not only does it use the patient’s own cells, but it obviates the need for a donor, and prevents any risk of an immune attack on the patient.

A few patients have been treated for cancer already using CRISPR, mostly in China but at least two in the US. other genetic diseases are being considered for this technology. A patient with another blood disorder called thalassemia has already been treated in Germany using CRISPR by the same company, CRISPR Therapeutics, which is sponsoring the current study. The company is encouraged by the first signs that this earlier treatment seems to have started to work in the thalassemia patient, who has now gone four months without a transfusion, and whose tests show that the infused modified cells have begun to function normally in the bone marrow.

Frangoul sums it up: “This opens the door for many patients to be treated and to have their disease modified to be mild.” Gray offers the patient’s viewpoint: “Being able to wake up and not be in pain. To be with my kids and see them grow up. That means the world to me.”