Three HIV-positive people received a cure using CRISPR
The CRISPR gene editing technology has already been used to modify animals, change the genes of babies and also to treat people with sickle cell disease. Now scientists are trying another novelty: They want to use CRISPR to permanently cure patients of HIV.
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In a remarkable experiment, the US biotechnology company Excision BioTherapeutics says it has introduced a tailor-made CRISPR tool into the bodies of three HIV-infected people. His mission: to cut and destroy the virus wherever it hides.
The pilot study is a first step toward the company’s goal of curing HIV infections with a single intravenous dose of the gene-editing tool. According to Excision Biotherapeutics, which is based in San Francisco, the first patient was treated about a year ago. At the end of October, doctors involved in the study reported at a meeting in Brussels that the treatment appears to be safe and has no major side effects. However, they withheld early data on the effects of the treatment, leaving experts outside the study only guessing as to whether the treatment worked.
“This is an extraordinarily ambitious and important study,” says Fyodor Urnov, a genome editing expert at the University of California, Berkeley. But it “would be good to know sooner rather than later” what the effect was, “including, possibly, no effect.” Failure would not surprise anyone familiar with HIV. The virus has proven to be a treacherous opponent: 40 years after its discovery in 1983, there is still no vaccine against it.
After all, pharmaceutical companies have developed so-called antiretroviral drugs that prevent the virus from copying itself. By taking these tablets, people with HIV can lead a normal life. However, if treatment is interrupted, the virus will rapidly reemerge, leading uncontrolled to the deadly syndrome of infection and cancer known as AIDS.
Hidden virus
One reason the virus cannot be completely eradicated with drugs alone is that it inserts its genetic material into the DNA in our cell nuclei, leaving behind hidden copies that can trigger the infection again. “All of a sudden the cell discovers, ‘Oh, my God, there’s a segment that contains the entire viral gene,'” says Kamel Khalili, a professor at Temple University in Philadelphia who co-founded Excision and continues to advise the company.
Vaccine manufacturers have also struggled because HIV attacks and kills the very immune cells called CD4+ that are supposed to prevent infections. A decade ago, however, Khalili realized that CRISPR could offer a way to cure the infection without involving the immune system: by deleting the virus’s genes in their hiding places. “If the viral gene is in the DNA, it’s like a genetic disease,” he says. “So you could use a genetic tool.”
CRISPR technology was developed in 2012 and its inventors have already been awarded the Nobel Prize. It was based on the discovery of molecules that bacteria use to recognize and destroy invading viruses – the so-called phages. CRISPR was quickly adapted for cutting human DNA, giving rise to the current era of human genome editing.
Most of the studies receiving attention today are aimed at treating hereditary diseases that arise when people are born with faulty DNA. CRISPR variants tailored to each condition can correct or remove these genes. A corresponding treatment for sickle cell anemia is expected to be approved this year.
Borrowed from nature
Excision’s study is unusual in that it attempts to eliminate those of a virus rather than human genes. Of the more than 50 gene editing studies in human volunteers that the MIT Technology Review evaluated this year, only two involved infectious diseases. However, Khalili notes that CRISPR’s original purpose in the wild was to knock out viruses. “Although the concept of using CRISPR against a virus seems novel, it goes back to what was already happening in nature,” he says.
Initial laboratory tests showed that CRISPR could detect and destroy the HIV genes in cells. Later, about 20 percent of HIV-infected mice that had a gene-editing agent instilled into their veins were functionally cured, Khalili said.
The company received permission to conduct human testing. So far three people have received the treatment. They were given an infusion of billions of harmless carrier viruses that contained DNA instructions for making and aligning the CRISPR scissors.
According to Excision, the treatment did not cause any major side effects. Because the approach appears to be safe, the company said it will continue the trial next year with higher doses, with six more patients receiving three and then 10 times the amount previously administered.
Data on the results is still pending
What is still missing is data on whether the treatment works. Patients in the study were taking antiretroviral medications, but the plan called for doctors to stop those medications 12 weeks after the gene editing treatment to see whether or not the virus returned. This step is known as “analytic treatment interruption.” If the virus didn’t return, it could mean that CRISPR had destroyed the viral genes.
The company apparently already knows the data for two of the patients who were treated months ago. But William Kennedy, senior vice president of clinical development at Excision, said the third patient was only recently treated and that full results for that group won’t be released until 2024.
That’s a long wait considering how quickly gene editing is evolving. According to Urnov, genetic engineering companies are particularly cautious due to the difficult financial environment. Some have seen their stock prices fall, and one, Beam Therapeutics, laid off 20 percent of its employees last week and said it would reorganize its efforts.
Khalili, who is not involved in the Excision clinical trial himself and therefore does not know the results firsthand, says the study could be just one step on a longer path to a cure. One that could eventually include the combination of multiple strategies.
“Even if we [HIV] “If we don’t cure it completely, we could significantly delay the resurgence of the virus,” he says. “That could prepare us for the next phase, as with any drug where there is a first and a second generation.”
(jl)
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