In 2014, Temple University researchers proved they could use state-of-the-art molecular scissors to cut out dormant HIV hiding in human cells in lab dishes.
Now, seven years later — the blink of an eye in basic research — the approach has received Food and Drug Administration approval for testing in humans, buoying hopes for curing, not just suppressing, the insidious virus that causes AIDS. Although the world is focused on the COVID-19 pandemic, HIV/AIDS continues to rage in many poor countries 40 years after it was identified.
“We’ve done a lot of preclinical work. Now we’ve shown it works in large animals,” said Tricia Burdo, a cell and molecular biologist at Temple University’s Katz School of Medicine. “It’s really exciting for Excision to bring this to the clinic.”
Excision BioTherapeutics was cofounded about five years ago by Kamel Khalili, the Temple microbiologist and immunologist who first explored using the gene-editing technology, called CRISPR, to remove HIV DNA from host cell DNA.
Excision has raised $60 million to fund clinical trials, hopefully starting by the end of the year with a small trial focused largely on safety. Temple, as well as Khalili and Burdo, have various financial interests in the company and the viral gene-editing technology.
After the successful “proof of principle” study, Khalili and his team in 2016 used CRISPR in another important lab dish experiment. They removed HIV DNA from the type of human immune cells where the virus can maintain a tiny reservoir of latent infection, even as HIV drugs suppress it to undetectable levels. That’s why curing HIV has been such an elusive goal.
The next year, 2017, they snipped HIV out of the genetic code of mice. The gene editing was effective in two mouse models — one representing a newly acquired infection, when the virus is actively replicating, the other representing chronic, or latent, infection.
By then, Burdo had been recruited from Boston College because she was an expert in the necessary next step: moving the approach into a non-human primate.
That study, published last November in the prestigious journal Nature, involved macaque monkeys infected with SIV, the simian version of HIV. The experiment was recently repeated in another non-human primate, Khalili said.
The researchers have shown that CRISPR — made of a synthetic “guide RNA” that searches for the targeted genetic code and an enzyme that acts like molecular scissors — persists in the cleared cells, thus preventing reinfection by HIV.
The approach is also one-and-done — a single intravenous infusion.
“Our strategy from the get-go was to make it easy to be given, not just in well-equipped labs,” Khalili said. “If this works, it could be taken anywhere,” including sub-Saharan Africa, where HIV infection is rampant. In 2018, there were 800,000 new HIV infections there, just under half of the global total, according to UNAIDS.
However, the genetic editing does not completely eradicate HIV. In the macaques, for example, CRISPR’s efficiency was 37%, 65%, and 92%, depending on the region of the viral genome that was being snipped out. In the mouse model, two-thirds of the mice still had some latent infection. That raises the question: How good is good enough?
“That’s the question in the [research] field: Do we need to completely eliminate every viral copy to achieve the cure?” Burdo said. “We don’t know yet.”
A number of labs around the world have been studying the use of gene-editing technology in HIV therapy.
Khalili speculated that eliminating all or most virus capable of replicating, even if latent virus remains, would achieve what scientists call a “functional cure.”
“With the Berlin patient, the virus wasn’t completely eliminated,” Khalili said, referring to Timothy Ray Brown, the first person cured of HIV when he was given a bone marrow transplant in 2007 from a donor who was naturally resistant to HIV. (Brown died last year at age 54 of a recurrence of the cancer that originally prompted the transplant.)
“Cleaving segments of viral DNA to cripple the virus may be enough for a functional cure,” Khalili said.