Breaking down how the gene editing technology is being used, for the first time in the United States, to treat patients with severe medical conditions


Last fall, the birth of genetically edited twin girls in China—the world’s first “designer babies”—prompted an immediate outcry in the medical science community. The change to the twins’ genomes, performed using the gene editing technology CRISPR, was intended to make the girls more resistant to H.I.V. But the edited genes may result in adverse side effects, and the International Commission on the Clinical Use of Human Germline Genome Editing is currently working on stricter and less ambiguous guidelines for editing the DNA of human embryos as a response to the rogue experiment.

Human genetic engineering has also witnessed more regulated advances. In the past 12 months, four clinical trials launched in the United States to use CRISPR to treat and potentially cure patients of serious medical conditions.

CRISPR-Cas9 is a technology derived from single-celled prokaryotic microorganisms and is composed of guide strands of RNA as well as the Cas9 enzyme, which does the “cutting.” It allows scientists to make changes at highly specific locations in a cell’s genetic code by removing or replacing parts of the genome. Even tiny changes to individual genes can fundamentally alter the function of a cell. CRISPR has been used to edit all types of organisms, from humans to corn, but clinical trials represent a stride toward turning the technology into a drug or medical treatment.

The clinical trials in the U.S. are Phase 1 and 2 trials, small studies designed to demonstrate the safety and efficacy of a potential treatment. Essentially, these make-or-break trials take a drug from the laboratory to test on real patients. They’re “the first requirement for a product to end up on the market,” says Saar Gill, an assistant professor at the University of Pennsylvania’s medical school who works on genetically-edited immune cells.

While some of the diseases CRISPR therapies aim to tackle have other treatments available, part of gene editing’s allure lies in the possibility of a more effective or even permanent fix. The four U.S. clinical trials involving CRISPR have the potential to tackle cancers such as melanoma and lymphoma, sickle cell disease, and even blindness.

“As complicated and expensive as [genetic editing] is, you really are talking about the potential to cure a disease or essentially halt its progress or its adverse effect on the body forever,” Gill says.

Editing Patients’ T Cells to Fight Cancer

The first clinical trial in the U.S. to use CRISPR in a treatment began last September. Led by University of Pennsylvania professor of medicine Edward Stadtmauer, it consists of genetically modifying patients’ own T cells—a type of immune cell that circulates in the blood—to make them more efficient at fighting certain kinds of cancer cells. The 18 patients will have types of relapsed cancer, like multiple myeloma or melanoma, that tend to overproduce an antigen called NY-ESO-1.

Once the T cells have been extracted from the patients’ blood, scientists will make several edits using CRISPR as well as a genetic modification technique derived from viruses like H.I.V. An added gene will cause the modified T cells to target cells with NY-ESO-1 as if it were a microscopic signal flare.

Another edit will stop T cells from producing proteins that could distract the cells from targeting NY-ESO-1. And researchers will also aim to turbo-boost the T cells by eliminating a protein called PD-1 that can prevent the T cells from killing cancer cells.

Patients will undergo chemotherapy to deplete their natural reserve of T cells, and then they’ll receive an infusion of the edited cells to replace them. The specific chemotherapy isn’t likely to affect the patients’ cancers, so that step of the trial won’t complicate the study’s assessment of the usefulness of T cell therapy.

According to a spokesperson for Penn Medicine, two patients—one with multiple myeloma and one with sarcoma—have already begun treatment. The trial is scheduled to conclude in 2033, and it will assess both safety (whether the edited T cell treatment leads to any negative side effects) and also efficacy (measured by outcomes such as whether the cancer disappears, the length of remission, and overall patient survival).

Boosting Fetal Hemoglobin in Patients With Sickle Cell Disease

A trial helmed by Massachusetts-based Vertex Pharmaceuticals and CRISPR Therapeutics is the first CRISPR-based clinical trial in the U.S. for a condition with a clear, heritable genetic basis: sickle cell disease. The recessive condition is caused by a single base-pair change, meaning that both copies of a patient’s affected gene differ by just one genetic “letter” from a normally functioning gene. Victoria Gray, a 34-year-old woman from Mississippi who was recently profiled by NPR, was the first patient to receive CRISPR-edited stem cells as part of the trial.

The disease, which occurs most frequently in people of African descent, affects a protein called hemoglobin, which plays a critical role in helping red blood cells carry oxygen to different tissues in the body. Sickle cell causes hemoglobin proteins to clump into long fibers that warp disc-shaped red blood cells into sickle shapes. The irregularly shaped blood cells are short-lived and can’t flow smoothly through blood vessels, causing blockages, intense pain and anemia.

Like the University of Pennsylvania T cell study, the sickle cell trial involves editing a patient’s own cells ex-vivo, or outside of the body in a lab. Stem cells are collected from the bloodstream and edited with CRISPR so they will pump out high levels of fetal hemoglobin, a protein that typically dwindles to trace levels after infancy. Fetal hemoglobin (HbF) is encoded by an entirely different gene than beta-globin, the part of hemoglobin that can cause red blood cells to sickle. Adults with sickle cell whose bodies naturally make more HbF often experience less severe symptoms. Fetal hemoglobin can take one or both of sickle hemoglobin’s spots in the four-part hemoglobin molecule, substantially lowering a cell’s likelihood of adopting a sickle shape.

The trial, slated to conclude in May 2022, will destroy participants’ unedited bone marrow cells with chemotherapy and then inject edited stem cells through a catheter in a onetime infusion. Doctors will look for the treatment to generate 20 percent or more HbF in the bloodstream for at least three months. Fetal hemoglobin normally constitutes only around 1 percent of adults’ hemoglobin supply, but previous studies have shown that proportions of fetal hemoglobin above 20 percent can keep enough cells from sickling to significantly reduce symptoms, including severe pain episodes.

If successful, the therapy would offer another option for a disease with few available treatments. The only current cure for sickle cell disease is a bone marrow transplant, but, according to the National Heart, Blood, and Lung Institute, such transplants work best in children and the likelihood of finding a marrow donor match is low. Just two FDA-approved drugs for sickle cell currently exist, aimed at ameliorating the worst of patients’ symptoms, and one of them, hydroxyurea, also works by increasing fetal hemoglobin.

Editing Donor T Cells to Fight Lymphoma

The same companies behind the sickle cell treatment have also begun a trial to use CRISPR-edited T cells to treat non-responsive or relapsed non-Hodgkin’s lymphoma. This cancer of the lymphatic system plays a major role in the body’s immune response. Unlike the University of Pennsylvania trial, the study involves editing T cells from donors. The cells will be edited using CRISPR to target CD-19, a protein that marks B cells, which become malignant in some types of non-Hodgkin’s lymphoma. The edits also remove two proteins to stop a patient’s immune system from rejecting the donated T cells and to prevent the edited T cells from attacking non-cancerous cells.

A researcher performs a CRISPR-Cas9 process at the Max-Delbrueck-Centre for Molecular Medicine. (Gregor Fischer / Picture Alliance via Getty Images))

A 2019 poster from the researchers explains that a prototype treatment in mice with acute leukemia stalled tumor growth for about 60 days. Additionally, lab tests showed that modified human T cells were successfully able to target and kill CD-19-marked cancer cells. For the clinical trial, which will eventually include a maximum of 95 participants, researchers will track how patients tolerate different doses of the T cell treatment and how many patients see their cancers shrink or disappear entirely. After the treatment is complete, scientists will keep tabs on patients and their survival and recurrence rates over the course of five years.

Editing Photoreceptor Cells to Treat Inherited Blindness

At the end of July, Cambridge, Massachusetts-based Editas Medicine, working with Irish company Allergan, announced that they’d begun enrollment in a clinical trial for EDIT-101, a treatment for a type of inherited childhood blindness known as Leber Congenital Amaurosis (LCA). It will be the first instance of a CRISPR clinical trial that conducts cellular editing within a human body, or in vivo. The trial will include about 18 participants, including patients as young as age 3, with a particular subset of LCA caused by a single genetic mutation that impairs photoreceptors. These cells in the eye convert light into signals for the brain to process.

The treatment comes in the form of an injection into the space behind the retina. A type of virus known as an adenovirus will “infect” the photoreceptor cells with DNA instructions to produce Cas9, the CRISPR enzyme, to cut the photoreceptor genome in specified locations. The edits change the photoreceptors’ DNA to fix the blindness-causing mutation, spurring the cells to regrow previously faulty light-sensing components, which should improve the patients’ vision.

Medical researchers aim to affect 10 percent or more of the targeted photoreceptor cells, the threshold that other research suggests is required to make a leap in visual acuity. Medical staff will measure patients’ vision in various ways, including an obstacle course featuring barriers with different contrast levels, a color vision test, the pupil’s response to light, and the person’s own assessment of visual change.

The EDIT-101 treatment has been tested in non-human primates and also in tiny samples of a donated human retina. In the human retina, the desired edit was made about 17 percent of the time, and scientists detected no unintended “off-target” changes.

The method of injecting a virus subretinally to treat LCA has been successful before. Jean Bennett and Albert Maguire’s treatment Luxturna doesn’t involve CRISPR, but it does use a similar viral injection to deliver a working copy of a malfunctioning gene to pigment cells in the retina. The work was recognized by Smithsonian magazine’s 2018 Ingenuity Award for life sciences.

The Future of CRISPR in Medicine

Early clinical trials are not without risks. In 1999, an 18-year-old participant named Jesse Gelsinger died in a Phase 1 gene therapy trial—a tragedy that still lingers over the field. Gelsinger had inherited a metabolic disorder, and like other patients in the trial, received an injection straight to his liver of the ammonia-digesting gene his body lacked. Four days later, multiple organs failed, and Gelsinger was taken off life support. After his death, investigations uncovered a tangle of ethical lapses. Critics said inadequate information had been provided about the study’s risks and pointed out that a key administrator at the University of Pennsylvania center behind the study had a financial conflict of interest.

Mildred Cho, a bioethicist and professor at the Stanford School of Medicine, sits on NExTRAC, the panel that advises the National Institutes of Health (NIH) on emerging biotechnologies. She says she’s “concerned that the factors at play in Jesse Gelsinger’s death have not actually been eliminated.” Specifically, Cho is wary of the risks of clinical trials moving too quickly in an environment where patients, physician-scientists and pharmaceutical companies alike are anxious to alleviate devastating medical conditions. “I think there’s a lot of pressuring pushing these new technologies forward, and at the same time, there’s more reluctance to regulate,” she says.

In the U.S., the current scientific consensus is that CRISPR is worth the risk, particularly to treat serious diseases with few alternative options. Other gene therapies have been successful before, like the cancer treatments Kymriah and Yescarta. But unlike most other gene editing techniques, CRISPR is relatively easy to engineer and use, opening up the floodgates for possible applications. The potential of tools like CRISPR to cure currently unfixable diseases represents a “massive paradigm shift from taking a pill for the rest of your life,” Gill says.

CRISPR is no miracle cure, yet. Larger trials must follow this preliminary work before the FDA can approve any new treatment. James Wilson, the former director of the University of Pennsylvania center that ran the trial in which Jesse Gelsinger died, said in a recent interview: “It’s going to be a long road before we get to the point where editing would be deemed safe enough for diseases other than those that have really significant morbidity and mortality.”

But for conditions that often prove deadly or debilitating, a little genetic engineering, done properly, could go a long way.

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