Imagine you’re 27 years old and you start feeling ill. Ill enough that you go to the hospital, and after much poking and prodding and waiting for lab results you learn you’re HIV positive. Two weeks later you find out that’s not even the worst of it. You’ve got leukemia too.
Under any circumstances it would be a lot to take in. Especially in China, where HIV/AIDS is highly stigmatized. But for one young man living there, who this happened to in the late spring of 2016, there was one small but significant silver lining to this double whammy of a diagnosis. He would be eligible to participate in the first-ever clinical trial to assess the safety of trying to cure both the cancer and the infection in a single procedure using the gene-editing tool called Crispr.
In July of 2017, doctors in Beijing blasted the patient with chemicals and radiation to wipe out his bone marrow, making space for millions of stem cells they then pumped into his body through an IV. These new stem cells, donated by a healthy fellow countryman, would replace the patient’s unhealthy ones, hopefully resolving his cancer. But unlike any other routine bone marrow transplant, this time researchers edited those stem cells with Crispr to cripple a gene called CCR5, without which HIV can’t infiltrate immune cells.
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Now, more than two years later, the patient is in good health, his cancer in full remission, as researchers report today in the New England Journal of Medicine. The edited stem cells survived and are still keeping his body supplied with all the necessary blood and immune cells, and a small percentage of them continue to carry the protective CCR5 mutation. Not enough to have cured him of HIV, though—he remains infected and on antiretroviral drugs to keep the virus in check. Still, experts say the new case study shows this use of Crispr appears to be safe in humans and moves the field one step closer toward creating drug-free HIV treatments.
“The safety profile appears to be acceptable,” pioneering cancer researcher Carl June wrote in an accompanying editorial, noting that the editing appeared to be precise, and that the engineered stem cells didn’t provoke an immune response in the patient. June did offer a caveat that the study’s single patient offered only limited data to draw on.
This is the first time an HIV-positive patient has been treated with Crispr-edited cells. But scientists have been trying to find ways to genetically disable CCR5 for more than a decade now. It all started in 2007, when a German doctor took a 41-year-old man with HIV/AIDS and leukemia off of his antiretroviral drugs and hooked a thin tube up to a vein in his chest. Through it, the so-called Berlin Patient received blood cells from a bone marrow donor who had a naturally occurring mutation called CCR5 Δ32. He was missing a chunk of DNA that ultimately allows an HIV virus to enter immune cells. The patient survived his cancer and became the first (though no longer the only) person considered to be fully cured of HIV/AIDS.What he found more striking was how quickly the science has moved from the first reports of using Crispr to treat HIV infection in mice to trying it in humans: only two years. At the University of Pennsylvania, June has led work in a groundbreaking cancer treatment called CAR-T, which involves genetically reprogramming immune cells into a clone army of tumor-targeting assassins. But it took him five years to go from studies in animals to trials involving humans. In this case, China’s more permissive biomedical research regulations might have expedited the work, or it could be that genetic engineering is lending new momentum to the race for an HIV/AIDS cure, he wrote. “In any case, the genie is out of the bottle with genome editing.”
Until that moment, scientists had only hoped to control the insidious disease, through drugs like PrEP that cut down on transmission or antiretroviral treatments that prop up patients’ immune systems. The Berlin Patient made them believe total virus annihilation was, in fact, possible.
His story galvanized labs and companies across the world to do it using genetic engineering. In 2009, California-based Sangamo Therapeutics launched the first human trials of gene-editing to treat HIV, using an older technology called zinc-finger nucleases. Those trials, which edit a person’s T cells, have produced some limited successes.
A better approach, many contend, is to instead edit the cells that make T cells (and all the other blood and immune cells) deep inside a person’s bones. Known as hematopoietic stem cells, they tend to be more resistant to editing, and require more risk and discomfort to deliver. But if you succeed, you can provide a patient with a lifetime supply of HIV-immune blood and immune cells. That’s what Crispr seems to offer.
The Chinese research team that conducted the latest study had previously transplanted Crispr-edited CCR5 mutant human cells into mice, making them resistant to HIV infection. In the spring of 2017 they registered a small human trial, to be conducted at the 307 Hospital of the People’s Liberation Army in Beijing. So far, the researchers have only enrolled and treated the single patient, according to Hongkui Deng, director of Peking University’s Stem Cell Research Center and one of the study’s coauthors. But Deng expects the trial to expand once they improve the efficiency of their technique.
To edit the donor stem cells, Deng’s team put them into a machine that applies a mild electrical shock. This allows the Crispr components—a DNA-chopping enzyme and GPS guides that tell it where to cut—to slip through the cell membrane and get to work. This approach minimizes potential mistakes, known as off-target effects, because Crispr is only in the cells for a short period of time, meaning they aren’t as likely to go rogue and break DNA they’re not supposed to. But it also means not all the cells get edited.
In an ideal world, both copies of the CCR5 gene would get snipped in all of the 163 million or so stem cells they isolated from the donor’s bone marrow. That would replicate what the Berlin Patient received from his donor. What the researchers got instead was much lower. After transplantation, only between 5.2 and 8.3 percent of the patient’s bone marrow cells carried at least one copy of the CCR5 edit. (The study authors didn’t report how many cells had both copies versus one copy edited.)
That number stayed more or less stable over the 19 months that researchers have so far tracked the patient. But the more telling question is whether T cells in the patient’s blood also retain the edit. In the specific kind of T cells that HIV uses to infiltrate the immune system, the broken version of CCR5 was present in only about 2 percent of them.
“That leaves a lot of room for improvement,” says Paula Cannon, a molecular microbiologist who studies HIV and gene-editing at the University of Southern California’s Keck School of Medicine. “At those levels, the cells would not be expected to have much of an effect against the virus.”
Another clinical trial, run by the City of Hope in Los Angeles, is investigating using zinc-finger nucleases to edit the hematopoietic stem cells of HIV-positive people, with a less aggressive bone-marrow-clearing-out step, what you might call “chemo-lite.” So far six patients have been treated, and again, after 500 days only about 2 to 4 percent of cells carried the mutation, according to data presented at an HIV/AIDS conference last month in Seattle.
“Ultimately, it comes down to the editing efficiency. That’s the biggest challenge right now,” says Rowena Johnston, vice president and director of research for amfAR, the Foundation for AIDS Research. Since 2010, the organization has awarded nearly $65 million to researchers working on HIV/AIDS cure strategies, including gene editing. “Crispr is certainly looking like the future right now, so I’m very interested these researchers decided to go in this direction.”
China has been pushing the boundaries of Crispr in humans since the tool arrived in bioengineers’ toolboxes. Last year, a scientist named Jiankui He scandalized the scientific world by using Crispr to edit CCR5 in human embryos, in an attempt to make children immune to HIV. The experiments crossed a plethora of ethical lines, in addition to not working that well. In response to the global outcry, China proposed new, stricter, regulations on gene-editing in humans.
Deng wouldn’t say whether the incident has made his own work more difficult, only that he has to be extra careful in how he explains it to the public. “Specifically, that in our study, gene-editing was applied to adult cells,” he wrote. Importantly, that means the CCR5 gene will remain unaltered in non-blood cell tissues. Studies have found that people lacking a functional CCR5 gene in all their cells are more susceptible to influenza and West Nile virus, and might even experience shortened lifespans.
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