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An An HIV-positive man in China is doing well after receiving donor cell infusions whose genes were modified with CRISPR 19 months ago, scientists said Wednesday in the New England Journal of Medicine. This makes him the most respected individual ever with CRISPR treatment, a genetic technology that has raised hopes for the treatment of the disease and has generated a multi-billion dollar industry in just four years.
The mere survival of the patient, apparently devoid of the side effects of a treatment that, according to some studies, could cause cancer or other disastrous genetic damage, provides assurance that CRISPR-based treatments could be safe – and mask the fact that the intervention was well below its goal. goal: to eliminate HIV from the cells of the man.
"They tried a moonpipe and, although they did not land on the moon, they went home safely," said Fyodor Urnov of the University of California's Innovative Genomics Institute. , Berkeley, who had previously participated in a study on Sangamo Therapeutics (SGMO). ) whether older genetic technology, zinc fingers, could cure HIV / AIDS. Urnov said about the Chinese study: "They explained how to get to the moon."
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It is rare but not unknown for the New England Journal to publish articles describing a single patient. They do, said spokeswoman Julia Morin, "when the conclusions warrant it".
The 27-year-old was diagnosed with HIV / AIDS in May 2016, and two weeks later, with additional tests, he had acute lymphoblastic leukemia, scientists said. The man has received standard AIDS treatment, antiretroviral therapy (ART), as well as chemotherapy for his form of leukemia, a cancer of the immune system's T cells.
But scientists have seen an opportunity for a stroke of chance: a cure for AIDS. Although ARV treatment maintains control of the virus, it does not eliminate the HIV that lurks in the cells, so patients must take antiretroviral therapy for the rest of their lives.
Fortunately, however, scientists discovered a dozen years ago that blood-donating cell transplants and immune cells, called hematopoietic stem and progenitor cells (HSPCs), can cure AIDS if their genome contains a mutation of the CCR5 gene that blocks a common gene. form of HIV from infective cells.
The "serendipity" arose from the fact that the 2007 "Berlin patient", Timothy Ray Brown, with AIDS and leukemia, received a bone marrow transplant for the latter. It turns out that the donor cells carry the CCR5 mutation blocking HIV. Brown, who was treated in Berlin, has been cured of leukemia and AIDS and has not taken antiretroviral therapy since his cell transplant.
Deng, who received his doctoral degree One of the most renowned biologists in China, from the University of California at Los Angeles, explained that if hematopoietic stem cells naturally carrying the CCR5 mutation could cure AIDS, those whose CCR5 gene is disturbed could do the same.
Since transplantation of HSPC from a healthy donor is a standard treatment for acute lymphoblastic leukemia, the benefit / risk ratio was much clearer than if the patient had only AIDS: he In any case, the cell graft was received, so that only the status of CCR5 cells would be different. .
Deng and his colleagues have published hematopoietic stem cells from a healthy bone marrow donor. They provided the CRISPR molecules – a target-finding guide RNA and a DNA-cutting enzyme – not via a virus, as do other experimental CRISPR therapies, but by "electroporation", using a current to pierce a tiny opening in the cells. The fixture was designed to disable the CCR5 gene to prevent HIV from entering the cells, as if a locked room prevented visitors from going through a key.
As is typical with CRISPR, only a fraction of the cells have been successfully modified. When Deng and his colleagues tested the hematopoietic stem cells before injecting them to the patient, they found that 17.8% of them had no functional CCR5, as expected.
Once the published stem cells were perfused into the patient and settled in his bone marrow, a series of measurements over time showed that only 5.2% to 8.28% of his bone marrow cells stem cell progeny had been modified as planned.
In an email interview, Deng acknowledged that it was a "low efficiency of gene editing in the patient". The probable explanation is that many of the infused edited cells do not survive and are therefore much less numerous than unedited donor cells or even cells. that of the patient.
His leukemia entered remission after cell transplantation. But the small fraction of cells published by CCR5 was insufficient to control its viral load. When the researchers removed the patient from antiretroviral therapy seven months after the stem cell transplant, with his consent, the number of people infected with HIV increased and the number of healthy T cells decreased. He returned under ART.
An encouraging finding, however, is that the percentage of cells edited by CCR5 has increased during the leave period. Previously, the level of CCR5 disruption in T cells in the blood was 2.96%, Deng told STAT, and this one "peaked at 4.39% during the interruption". Unfortunately, he continued, "the optimal efficiency of gene editing is 100%, suggested by the case of a Berlin patient."
Two scientists not involved in the study questioned the decision to transplant stem cells while few had been successfully published.
It has been known for years "that CCR5 is more effective and responds effectively," said Urnov of Berkeley. "They chose to treat a subject with cells whose editing was less than 20%. This is not a decision I would have made. The fact that they have failed to control HIV is not "surprising", he said, but does not "negatively reflect the approach".
In fact, low publishing rates could be significant. In the Sangamo study using zinc fingers to edit CCR5, 12 HIV-positive patients received a single dose of 10 billion T-lymphocytes. Between 11% and 28% of the cells were modified as expected, no longer producing normal CCR5 . Patient rates of a type of T cell that HIV kills, called CD4 T cells, have increased, suggesting that gene-modified T cells do not contain but are proliferating, reported Sangamo in 2014. Although Sangamo concluded that the treatment was safe and that the company has conducted a larger clinical trial, it no longer pursues this program but focuses on genome editing for sickle cell disease and other disorders. blood.
Deng nonetheless called the writers of himself and his colleagues to have realized "a promising approach to gene therapy" of HIV / AIDS. "The cells carrying the modified CCR5 gene persisted" for 19 months and counted, even at low levels, he said, and CRISPR reached the targeted target and no others, as far as the researchers were able to determine by sequencing of the genome. This suggests that CRISPR did not crash, removing for example cancer suppressor genes.
Until now, there is only one patient in the study, said Deng. But "we plan to improve the efficiency of the hematopoietic stem cell editing and optimize the transplant protocol based on this patient," he said, guided to the both by his findings and those of studies on the mouse that he had reported with his colleagues in 2017. This experiment, they wrote, "Provides evidence for the modified CCR5 translation. [hematopoietic] transplant to heal HIV at the clinic. "
Deng was born in China and graduated from the university. After receiving his doctorate at UCLA in 1995, he worked as a postdoctoral fellow on HIV at New York University. In 1998, he became research director of Boston-based ViaCell Stem Cell Biotech. He was brought back to China in 2001 by a prestigious pulpit at Peking University, where he first worked on the use of human embryonic stem cells to treat diabetes. In 2006, he won $ 1.9 million in Grand Challenges in Global Health from the Bill and Melinda Gates Foundation for HIV and Hepatitis C Vaccine Research.
Not everyone agrees that CRISPR is ready for use in HIV / AIDS patients. "In my opinion, it is too early to go to the bedside of the patient," said biologist Shuliang Chen of the Ohio State University and Wuhan University, co-author of a recent journal on gene editing for HIV / AIDS. On the one hand, disabling CCR5 prevents a single strain of HIV, not all. More generally, Chen said, "We need more evidence regarding security, out-of-target effects, and the targeted effectiveness of CRISPR."
But there is a bigger problem. "In most cases, HIV patients live well with antiviral therapy," said Chen. Deng's patient was doing just that. The only justification for "editing high-risk genes," he said, is that they also have leukemia, in which case "gene-modified hematopoietic stem cells can be used." to kill two birds with one stone ".
Despite the caveats, there will be more experiences trying to cure HIV / AIDS with CRISPR. "It's not a total success," Urnov said, "but what to do and how to do it is now even clearer."
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