September 13, 2019

A patient with HIV/AIDS who received transplanted stem cells edited with CRISPR to have a mutation that blocks HIV is living without side effects, providing evidence that the gene-editing technology can safely target HIV, according to a case study published Wednesday in the New England Journal of Medicine (NEJM). The treatment did not cure the patient of HIV/AIDS.

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Background

In a groundbreaking discovery in 2007, researchers observed that a transplants of cells that produce blood and immune cells can cure AIDS if their genomes contain a mutation in the CCR5 gene that blocks a common form of HIV. The so-called "Berlin patient" received widespread attention.

The Berlin patient, Timothy Ray Brown, had AIDS and leukemia. He received a bone marrow transplant to treat his leukemia, and the donor cells he received contained the CCR5 gene that blocks HIV. The transplant cured Brown's AIDS and leukemia, and he has not taken antiretroviral therapy (ART)—treatment for HIV/AIDS—since the transplant.

New case study details

For the new case study, researchers at Peking University in China were presented with an opportunity to reproduce the Berlin patient's treatment by using CRISPR to edit the HIV-blocking CCR5 mutation into donor cells that were to be used to treat a leukemia patient with AIDS.

The patient is a 27-year-old male who was diagnosed with AIDS and leukemia in 2016. The patient, who had been treated with ART for AIDS and chemotherapy for leukemia, eventually needed a hematopoietic stem cell (HSPC) transplant to treat leukemia. This is standard treatment for leukemia, which according to STAT News, made "the risk-benefit balance" of the treatment "much clearer than if the patient had AIDS alone."

Before transplanting the leukemia fighting stem cells, the researchers used a technique called "electroporation"—the use of a current to make tiny holes in the cell—to edit the donor cells in a way that disabled the CCR5 gene so that HIV would be "locked" out of the cells.

Only some of the cells were successfully edited, which is expected with CRISPR. The researchers tested the cells before infusing them and found 17.8% had the mutation that disabled the CCR5 gene.

Key findings

After the researchers infused the edited stem cells into the patient and settled them into his bone marrow, measurements revealed that 5.2% to 8.28% of his bone marrow cells had the CCR5 gene mutation. The researchers said that figure was too low to control the patient's viral load and he later returned to ART to control his AIDS.

Still, the patient's leukemia entered remission after the transplant, and nineteen months after the transplant, the patient has no side effects. According to STAT News, the fact that the patient survived, and apparently without side effects that could have included cancer or genetic damage, suggests CRISPR-based therapies may be safe.

Discussion

While the experiment did not cure the patient of AIDS, the evidence it provides regarding the safety of CRISPR-based therapies is being heralded as a major development. According to STAT News, NEJM rarely publishes papers describing a single patient. An NEJM spokesperson said the publication does so "when the findings warrant it."

Hongkui Deng, a professor of cell biology at the Peking University, who helped lead the research, said, "[W]ith this report, we have partial success." He added, "It tells you the feasibility and the safety is quite promising for the gene-editing approach."

Similarly, Fyodor Urnov of the Innovative Genomics Institute at the University of California, Berkeley, said the researchers "attempted a moonshot, and while they did not land on the moon, they got back home safely." He added that the study "highlighted how to get to the moon."

Carl June, professor in immunotherapy at the University of Pennsylvania and a gene therapy pioneer who wrote an editorial accompanying the case report, said, "It's not a home run at this point, but getting to first base is really critical for this technology." He added, "We're going to see many, many applications now since they got to first base here on this one."

Still, some have noted caveats to the latest findings. Shuliang Chen of Ohio State University and Wuhan University noted that disabling CCR5 works against only one strain of HIV. "We need more evidence about CRISPR-related safety, off-target effects, and on-target efficiency," Chen said.

Further, the bigger issue, according to Chen is that most HIV patients "live well with antiviral drug treatment." He added that "high-risk gene editing" could only be warranted if patients also have leukemia and researchers "can use gene-edited hematopoietic stem cells to kill two birds with one stone" (Begley, STAT News, 9/11; Stein, "Shots," NPR, 9/11; Xu et al., New England Journal of Medicine, 9/11; Cortez/Brown, Bloomberg, 9/11).

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