When Victoria Gray was just a baby, she started barking so inconsolably during a bath that she was rushed to the emergency room. Her diagnosis was sickle cell disease, a genetic disorder that causes bouts of excruciating pain, “worse than a broken leg, worse than childbirth,” one doctor told me. Now 38 years old, Gray is like lightning crackling inside her body. explained the pain. For most of her life, she lived in fear that a seizure could occur at any time, forcing her to drop everything and rush to the hospital again.
After a particularly long and debilitating hospitalization during college, Gray became so weak that he had to relearn how to stand and use a spoon. She dropped out of school. She gave up on her dream of becoming a nurse.
Four years ago, she participated in a groundbreaking clinical trial that changed her life. She was the first sickle cell patient to be treated with the gene editing technology CRISPR and one of the first humans to be treated with CRISPR. Although her CRISPR was highly touted at that point, it was mainly used only for tinkering with cells in the lab. When Gray received an experimental IV drip, scientists didn’t know whether it would cure her disease or cause something seriously wrong inside her body. The treatment worked, and it worked better than anyone expected. Thanks to the gene-edited cells, Gray now lives almost symptom-free. 29 out of 30 eligible patients In this study, pain episodes that had occurred multiple times each year were reduced to zero within 12 months of treatment.
The results were so surprising that the treatment from Vertex Pharmaceuticals and CRISPR Therapeutics became the first CRISPR drug ever approved and was given the green light by UK regulators. early this month; The FDA appears poised to follow suit within the next two weeks. Although no one yet knows the long-term effects of this therapy, Ms. Gray is now healthy enough to work full time and care for her four children. “Now I’ll help my daughters choose their wedding dresses. And we’ll be able to take a family trip.” she told NPR 1 year after treatment. “And they will be with their mother every step of the way.”
This approval is a milestone for CRISPR gene editing. CRISPR gene editing was just an idea in an academic paper more than a decade ago, even though it had already been approved. cure an incurable disease and change the world. But how exactly? Shortly after publishing his seminal work, Jennifer Doudna, who shared the Nobel Prize in Chemistry with Emmanuel Charpentier for his pioneering CRISPR research, met with a doctor during a trip to Boston. He told her that her CRISPR could potentially treat sickle cell disease. On his computer, he scrolled through her DNA sequence from a sickle cell patient’s cells that the lab had already edited with her CRISPR. “For me personally, that was one of the watershed moments,” Doudna told me. “Okay, this is going to happen.” And now it has happened. Gray and patients like her are living proof of the power of gene editing. Sickle cell disease may be the first disease transformed by CRISPR, and perhaps the last.
The debilitating and ultimately fatal effects of sickle cell disease all result from a single gene typo. A small misspelling in Ms. Gray’s DNA (the A accidentally became a T) caused the oxygen-binding hemoglobin protein in her blood to clump together. As a result, her red blood cells had a hard, sticky, sickle-like characteristic that made them more likely to block her blood vessels. Where oxygen cannot reach tissue, it begins to die. “Imagine if you put a tourniquet on it and walk away, or if you always had a heart attack,” says Louis Hsu, a pediatric hematologist at the University of Illinois at Chicago. These blockages are extremely painful, and repeated attacks cause cumulative damage to the body that causes some sickle cell patients to die. On average, they are 20 years younger.
Not everyone with the sickle cell mutation gets very sick.as dating back to the 1940sOne doctor noticed that the blood of newborn babies with sickle cell disease was surprisingly less sickled. Babies in the womb are actually creating a fetal version of the hemoglobin protein, and its high affinity for oxygen draws the molecule from the mother’s blood. At birth, the gene that codes for fetal hemoglobin begins to turn off. However, adults may still produce varying amounts of fetal hemoglobin. Scientists observed that the more fetal hemoglobin produced, the more mild the sickle cell disease was, as if it were replacing defective adult hemoglobin. Geneticists have finally figured out exactly the series of switches that our cells use to turn fetal hemoglobin on and off. But there they remained stuck. They had no way to turn it on themselves.
Then along came CRISPR. The basic technology is genetic scissors, which cut DNA fairly precisely. CRISPR currently cannot fix the A-to-T typo that causes sickle cell, but it can be programmed to disable and turn back on the switch that suppresses fetal hemoglobin. chop snip snip It is made up of billions of blood cells, resulting in blood that functions like typical blood.
Sickle cells were a “very obvious” target for CRISPR from the beginning, said Hader Frangoul, a hematologist at the Sara Cannon Institute in Nashville who treated Gray in the trial. Scientists already knew the gene editing needed to cure the disease. Sickle cells also have the advantage of affecting blood cells, which are selectively removed from the body and can be genetically edited in the controlled environment of a laboratory. Meanwhile, patients receive chemotherapy that kills blood-forming cells in the bone marrow, and then the CRISPR-edited blood-forming cells are injected into the body, where they slowly take root and replicate over several months.
It’s a long, grueling process similar to a bone marrow transplant using your own edited cells.bone marrow transplant from donor Currently, it’s the only way doctors can treat sickle cell disease, but it comes with the challenges of finding a compatible donor and the risk of an immune complication called graft-versus-host disease. Using CRISPR to edit a patient’s own cells eliminates both obstacles. (A Second gene-based therapyuses a more traditional engineered virus technique that semi-randomly inserts a modified adult hemoglobin gene into DNA, and is expected to soon receive FDA approval for sickle cell disease. So far, CRISPR therapy has taken much less time to develop, although it appears to be equally effective at preventing pain attacks. )
But in another sense, sickle cell disease is also an unexpected front-runner in the race to commercialize CRISPR. Despite being one of the most common genetic diseases in the world, overlooked Who is affected: Globally, The vast majority of sickle cell patients Lives in sub-Saharan Africa. In the United States, about 90% They are of African descent, a group that faces discrimination in the medical field. When Gray, a black woman, needs powerful painkillers, she will be dismissed as an addict seeking drugs rather than a patient in crisis.common story Among sickle cell patients.
For decades, treatment for the disease was also delayed.Sickle cell disease is also known in Western medicine. since 1910but first medicine It wasn’t available until 1998, said Vance Bonham, a researcher at the National Human Genome Research Institute who studies health disparities. 2017Bonham began convening focus group Ask sickle cell patients about CRISPR. While many were hopeful, others were worried because of America’s history of experimentation on black people. Mr Gray said that if he had been offered an experimental plan at one of the hospitals where he was treated, he would never have agreed. She’s not feeling well. Several researchers told me they expect sickle cell therapy to make a different kind of history. Communities that have been marginalized in medicine will be the first to benefit from her CRISPR.
Doctors are still reluctant to call this a complete “cure.” The long-term durability and safety of gene editing is still unknown, and although the treatment has virtually eliminated pain attacks, organ damage can accumulate even in the absence of acute pain, Hsu says. . Could gene editing also prevent such organ damage?His Vertex, the company that makes the therapy, plans to monitor patients. 15 years.
Still, the short-term impact on patients’ lives is profound. “Five or 10 years ago, this would have been unthinkable,” said Martin Steinberg, a hematologist at Boston University and a member of Vertex’s steering committee. Masu. He thought it might improve pain crises, but could it eliminate them almost completely? It seems pretty close to a cure.
But Steinberg believes that in the future, this current state-of-the-art treatment may look like just a “crude experiment.” Because of the long and painful process required to kill unedited blood cells, the limited number of transplant centers in the United States are inaccessible to patients who cannot travel for months, making development difficult. Patients living with sickle cell disease in developing countries also cannot access it. . The field is already looking at techniques that can edit cells in the body, a milestone recently achieved in the liver. CRISPR trial lowers cholesterol. Scientists are also developing a more sophisticated version of his CRISPR than genetic scissors. DNA paste sequence or Edit one character at a time. Doctors may one day be able to directly correct the underlying mutation that causes sickle cell disease.
Such breakthroughs will enable CRISPR to treat diseases that are out of reach today, either because CRISPR cannot be introduced into the required cells or because editing is too complex. “I now receive emails every day from families all over the world asking, ‘My son or a loved one has this disease.’ Can CRISPR solve this?” said Frangoul, who is known as the first doctor to administer intravenous fluids to patients with hepatocytes. The answer is usually not yet available.but clinical trial CRISPR is already being tested in the treatment of cancer, diabetes, HIV, urinary tract infections, hereditary angioedema, and more. “We have opened the book on CRISPR gene editing, but this is not the final chapter,” Frangoor said. I may still be writing the first part.
