Your DNA is your body’s most closely guarded asset. To reach it, any would-be-invaders have to get under your skin, travel through your bloodstream undetected by immune system sentries, somehow cross a cell membrane, and finally find their way into the nucleus. Most of the time, that’s a really good thing. These biological barriers prevent nasty viruses from turning your cells into disease-making factories.
But they’re also standing between patients with debilitating genetic diseases and their cures. Crispr, the promising new gene editing technology, promises to eradicate the world of human suffering—but for all the hype and hope, it hasn’t actually cured humans of anything, yet. Medical researchers have the cargo, now they just have to figure out the delivery route.
The first US trials of Crispr safety are set to begin any day now, with Europe expected to follow later this year. Chinese scientists, meanwhile, have been testing Crispr humans since 2015, as the Wall Street Journal recently reported, with mixed success. These first clinical forays involve removing cells from patients’ bodies, zapping them with electricity to let Crispr sneak in, then infusing them back into their bodies, to either better fight off cancer or to produce a missing blood protein. But that won’t work for most rare genetic diseases—things like cystic fibrosis, Duchenne’s muscular dystrophy, and Huntington’s. In the 34 trillion-cell sea that is your body, an IV bag full of Crispr’d cells simply won’t make a dent.
This is the same problem that has plagued the stop-and-go field of gene therapy for nearly three decades. Traditional gene therapy involves ferrying a good copy of a gene inside a harmless virus, and brute-forcing it into a cell’s DNA. Crispr’s cutting action is much more elegant, but its bulk and vulnerability to immune attacks make it just as difficult to deliver.
“The challenge is getting gene editors to the right place at the right time in the right amount,” says Dan Anderson, an MIT chemical engineer and one of the scientific founders of Crispr Therapeutics. “That’s a problem people have been working on for a long time. As of today there certainly is no one way to cure every disease with a single delivery formulation.”
And it’s unlikely there will be anytime soon. So for now, most Crispr companies are taking more of a “whatever works” approach, borrowing mostly from gene therapy’s few success stories. One of those is a small, harmless helper virus called AAV, well-suited for carrying genetic instructions into a living cell. AAV won’t make you sick, but it can still sneak into your cells and hijack their machinery, making them a perfect Trojan horse in which to put good stuff—like a correct copy of a gene, or instructions for how to make the protein-RNA pair that forms the Crispr complex. Crispr’s instructions are quite long, so they often can’t fit inside one virus.
But once you get around that, there’s an even bigger downside to AAV; once it ferries Crispr inside a cell, there’s no good way to control its expression. And the longer Crispr hangs around, the greater the chance it could make unwanted cuts.
Delivering Crispr into the cell directly, as opposed to teaching the cell to build it, would provide more control. But doing that means enveloping the unwieldy, charged protein complex in a coating of fat particles—one that can simultaneously shield it from the immune system, get it across a cell membrane, and then release it to do its cutting work unencumbered. Although the technology is improving, it’s still not very efficient.
The Big Three—Crispr Therapeutics, Editas Medicine, and Intellia Therapeutics—as well as the latest newcomer, Casebia, are all investing in AAV and lipid nanoparticles, and testing both for their first rounds of treatment. “We’re leveraging existing delivery technologies, while exploring and developing the next generation,” says Editas CEO Katrine Bosley. “We will use whatever works best for a given target.”
But industry isn’t the only one feeling the urgency. This week the National Institutes of Health announced it will be awarding $190 million in research grants over the next six years, in part to push gene editing technologies into the mainstream. “The focus of the Somatic Cell Genome Editing program is to dramatically accelerate the translation of these technologies to the clinic for treatment of as many genetic diseases as possible,” NIH Director Francis Collins said in a statement Tuesday. Which could encourage some of the more exotic, experimental delivery systems out in the research world—strategies like Crispr-covered gold beads, yarn-like ball structures called DNA nanoclews, and shape-shifting polymers to get the editor where it needs to go.
In October, UC Berkeley researchers Kunwoo Lee, Hyo Min Park, and Nirhen Murthy used those gold nanoparticles to repair the muscular dystrophy gene in mice. They’re now expanding that work in a startup the trio co-founded called GenEdit. They plan to develop a suite of nanoparticle delivery vehicles optimized to different tissues, starting with muscles and the brain. Then they’ll partner with the folks making the Crispr payloads. That will make it the first company devoted solely to Crispr delivery. The gene editing world is filling up with products to deliver—but even Amazon needs UPS.