Scientists use gene-modified stem cells to treat HIV – with mixed success

For the first time, researchers used CRISPR gene modification technology to treat a person infected with HIV.

Chinese scientists have developed human stem cells to mimic a rare form of natural immunity to the virus and transplanted them into a man with HIV and a blood cancer. Cells modified by the gene survived in the human body for more than a year without causing detectable side effects, but the cell count was not high enough to significantly reduce the amount of HIV in the body. his blood.

"This is an important step in the use of gene editing to treat human diseases," says Fyodor Urnov, a biologist at the University of California, Berkeley. . "With this study, we now know that these modified cells can survive in a patient and stay there."

L & # 39; study¹ was published on September 11 in the New England Journal of Medicine. The lead author, Hongkui Deng, a biologist at Peking University in Beijing, said his research was inspired by a remarkable bone marrow transplant that had apparently healed a man with HIV there is more ten years.

Mutant power

In 2007, Timothy Ray Brown – initially called the "Berlin Patient" – underwent a bone marrow transplant to treat his leukemia. The bone marrow donor, however, had a peculiarity of having a version of the CCR5 gene that confers immunity to HIV.

Normally, the gene codes for a receptor on the surface of the white blood cells that the HIV virus uses to infiltrate the cells. But in people with two copies of CCR5 mutation, this receptor is deformed and prevents certain strains of HIV from entering the cells. The version of the HIV-resistant gene is exceptionally rare: it is found only in 1% of people of European descent and is virtually non-existent in other ethnic groups.

Doctors hoped that bone marrow transplantation would replace HIV-sensitive Brown blood cells with immune cells – and this is the case. After nearly 13 years, there is no sign of HIV in his blood and his leukemia is in remission. In March, researchers reported that a second person had undergone a similar procedure in Britain and had been cured.².

Deng wanted to use CRISPR gene editing to design blood stem cells from normal, HIV-resistant donors, making this potential treatment more widely available. He and his colleagues tested this approach on a 27-year-old man in China who had been diagnosed with HIV and leukemia and who needed a bone marrow transplant. The scientists extracted stem cells from the bone marrow of a donor and used CRISPR – Cas9 to transform them into CCR5 mutants.

At first, the researchers failed to convince CRISPR to knock out CCR5 in stem cells. "I thought, wow, these cells are really hard," says Deng. Finally, they were able to modify 17.8% of the donor stem cells.

Security first

To maximize the chances of the transplant treating the patient's cancer, the researchers mixed the modified stem cells with the unmodified ones. The team monitored the man after the transplant to see if the retouched cells survive and replicate, if they treat HIV infection and, most importantly, if the treatment is safe.

"It was the first try. The most important thing was to test the security, "says Deng.

The release of CRISPR genes in humans remains controversial, in part because many researchers are concerned about its side effects. Studies have shown that CRISPR sometimes creates undesirable mutations in the laboratory³ – and the consequences of what happens to a person could be disastrous.

After 19 months, CRISPR-modified stem cells persisted, although they represent only 5 to 8% of the total number of recipient stem cells. This means that just over half of the edited cells have died after their transplantation. And although human leukemia is in remission, he is still infected with HIV.

"I'm not surprised that 5% is not enough to reduce viral load," says Urnov, "but we now know that CRISPR-published cells can persist and we need to do more than 5%."

For Deng, the most important thing is that the man does not suffer any side effects caused by gene-modified cells. And when the researchers sequenced the genomes of these cells, they found no evidence of unintended genetic changes.

Pushing towards the front

"This is very good news for the field," says Carl June, an immunologist at the University of Pennsylvania in Philadelphia. "We now know that in principle we can use CRISPR to edit human stem cells, that they can persist in a patient and that this can be safe."

June states that this proof of concept opens the door to research on testing this technology for the treatment of other blood diseases, such as sickle cell disease. He also noted that this study complied with standard ethical protocols, including obtaining informed consent from the participant.

Thanks to improvements in gene modification technology, researchers can now modify stem cells with greater efficiency than the 17.8% success rate of the last study. But that entails risks. Whenever CRISPR cuts the genome, there is a chance that something will go wrong. Gene editing cells more effectively mean more cuts and more opportunities for error.

"This document is an incomplete success, but it will only motivate the sector to go forward," said Urnov. If the experiment proved dangerous, the regulators might have stopped future research. Now, he says, researchers can point to irrefutable evidence in this study that this line of research can be safe and potentially fruitful.

"I'm going to have an extra scoop of ice cream tonight, knowing that editing the human genome for the treatment of the disease is still going on," Urnov said.