How Crispr Could Snip Away Some of Humanity’s Worst Diseases


HIV has no cure. But it’s not quite the implacable scourge it was throughout the 1980s and 1990s. Education, prophylactics, and drugs like PrEP have cut down its transmission. Anti-retroviral treatments keep HIV-positive people’s immune systems from collapsing.

But still, no cure. Part of the problem is HIV’s ability to squirrel itself away inside a cell’s DNA—including the DNA of the immune cells that are supposed to be killing it.

The same ability, though, could be HIV’s undoing. All because of Crispr. You know, Crispr: The gene-editing technique that got everyone really excited, then really skeptical, and now cautiously optimistic about curing a bunch of intractable diseases. Earlier this week, a group of biologists published research detailing how they hid an anti-HIV Crispr system inside another type of virus capable of sneaking past a host’s immune system. What’s more, the virus replicated, and snipped HIV from infected cells along the way. At this stage, it works in mice and rats, not people. But as a proof of concept, it means similar systems could be developed to fight a huge range of diseases—herpes, cystic fibrosis, and all sorts of cancers.

Those diseases are all treatable, to varying degrees. But the problem with treatments is you have to keep doing them in order for them to work. “The current anti-retroviral therapy for HIV is very successful in suppressing replication of the virus,” says Kamel Khalili, a neurovirologist at Temple University in Philadelphia and lead author of the recent research, published in Molecular Therapy. “But that does not eliminate the copies of the virus that have been integrated into the gene, so any time the patient doesn’t take their medication the virus can rebound.” Plus treatments can—and often do—fail.

Gene therapy has promised to revolutionize medicine since the 1970s, when a pair of researchers introduced the concept of using viruses to replace bad DNA with good DNA. The first working model was tested on mice in the 1980s, and by the 1990s researchers were using gene therapies—with limited success—to treat immune and nutrition deficiencies. Then, in 1999, a patient in a University of Pennsylvania gene therapy trial named Jesse Gelsinger died from complications. The tragedy temporarily skid-stopped whole field. Gene therapy had been steadily getting its groove back, but the 2012 discovery that Crispr could make easy, and accurate, cuts on human genes, has added even more vigor.

Crispr as an agent for curing HIV has its own problems. For one, it has to be able to snip away the HIV from an infected cell without damaging any of the surrounding DNA. HIV mutates and evolves, so Khalili and his co-authors couldn’t just program their Crispr system with a single genetic mugshot. Instead, they had to target enough unchanging sections that were also critical to the virus’ survival.

Their next challenge was delivering the system to a critical mass of infected cells. First you have to get it past the immune system—which is programmed to attack any non-foreign object entering the body. They did this by packing their Crispr system inside another type of virus called AAV (short for adeno associated virus). “AAVs are a very small helper virus, they can’t actually replicate in a cell on their own unless they have another virus there to help it along,” says Keith Jerome, a microbiologist at the Fred Hutchinson Cancer Research Center in Seattle. “The great thing about AAVs is they cause essentially no immune system response in humans.” Although that’s not always true. Jesse Gelsinger died in 1999 because his immune system overreacted to the AAVs he’d been given in his gene therapy trial. So doctors hoping to prescribe AAV-based gene therapy have to be aware of patients’ prior exposure.

In order to get approved for human use, this type of Crispr-borne cure would have to be both safe and effective. This study got part of the way. This study was going strictly for efficacy: Does this work? Khalili and his co-authors treated mice and rat model with strains of HIV that were latent—hiding away in cellular DNA—and others where the HIV was actively replicating. Then they used it on mice grafted with human cells. In all three cases, the HIV rates went down significantly.

Other good news on the safety front: There’s no evidence their trial made any off-target cuts. But they’ll need to run more experiments to make sure that’s absolutely the case, probably using primate models, since their DNA is closer to humans’. They also have to make sure the treatment gets rid of enough HIV, so that it doesn’t just replicate itself back to harmful levels. “In actual human patients there’s no way that a Crispr gene therapy will ever get 100 percent of HIV,” says Paul Knoepfler, a stem cell biologist at UC Davis. “How highly efficient will be ‘efficient enough’ to make a clinically meaningful impact?”

Khalili believes he can get close enough. According to him, the Crispr system doesn’t need to eliminate all the HIV-infected cells—just enough so an HIV-patient’s immune system can get strong enough to take care of the rest on its own. “I strongly believe in the gene editing strategy, and with my 30 years in HIV research, I think this is the one that is going to take us to the end.”

He’s not the only optimist. “The advantage of using a virus as your delivery system is it can infect virtually every cell,” says Jianhua Luo, a pathologist at the University of Pittsburgh. Luo is using a similar Crispr-in-a-virus system to target cancerous DNA in cells.

And curing HIV could be a proof-of-concept for other diseases—even genetic diseases people are born with. Even though the virus starts as a simple infection, once it becomes part of a person’s chromosome, it essentially becomes a genetic disease. Imagine a world where, instead of removing her breasts, Angelina Jolie could instead have taken a dose of genes that snip away the BRCA2 genes that threatened her with cancer. That’s the difference between a treatment and a cure.

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