The Crispr components can’t get into cells naturally on their own, so Intellia uses a delivery system called lipid nanoparticles — essentially tiny sacs of fat — to deliver them to the liver. In Intellia’s studies, patients receive a single intravenous infusion of these Crispr-loaded nanoparticles into the veins of their arms. Because blood flows through the liver, lipid nanoparticles can easily get there from the bloodstream. In the liver, the nanoparticles are absorbed by so-called hepatocytes. Once inside these cells, the nanoparticles break down and let Crispr go to work removing the offending gene.
In both diseases, a genetic mutation allows an aberrant protein to run amok and cause damage. For hereditary angioedema, Intellia’s Crispr treatment is designed to turn off the KLKB1 gene in liver cells, thereby reducing the production of kallikrein protein. Too much kallikrein leads to overproduction of another protein called bradykinin, which is responsible for recurring, debilitating, and potentially fatal bouts of swelling.
According to an Intellia press release, patients experienced one to seven episodes of swelling per month prior to Crispr infusion. During a 16-week follow-up period, Crispr infusion reduced these attacks by an average of 91 percent.
In transthyretin amyloidosis, mutations in the TTR gene cause the liver to produce abnormal versions of the transthyretin protein. These damaged proteins build up over time, causing serious complications in tissues like the heart, nerves, and digestive system. One type of the disease can lead to heart failure and affects between 200,000 and 500,000 people worldwide. By the time patients are diagnosed with the disease, they are expected to live for only two to six years.
Intellia’s Crispr treatment is designed to inactivate the TTR gene and reduce the buildup of the disease-causing protein it produces. Vaishali Sanchorawala, director of the Amyloidosis Center at Boston University School of Medicine, says the reduction Intellia is reporting is exciting. “This has the potential to completely revolutionize the outcome for these patients living with this disease,” says Sanchorawala.
A big question is whether the changes will be permanent. In some patients, Crispr shows promise beyond a year, Leonard says. But liver cells eventually regenerate, and scientists haven’t observed patients long enough to know if new cells that split off from the edited ones will also harbor the genetic correction.
“What we do know is that if you edit a cell, it stays edited for its entire lifetime. There is no way to undo this. And when there is fluctuation, the question arises: Well, where do the new cells come from? In the case of the liver, it comes from other hepatocytes,” says Leonard. “We think once you have it in the upstream cell from which everything else follows, it’s forever.”
Scientists working on in vivo Crispr therapies have focused on the liver as an initial target because of the many genetic diseases associated with it. And because fats, like lipids, are easily absorbed by the liver, scientists at Intellia and elsewhere have found they can be used to get Crispr there.
Two other companies, Beam Therapeutics and Verve Therapeutics, are also using lipid nanoparticles to target the liver through gene editing. In July, Verve began a trial to treat a genetic form of high cholesterol using base editing, a more precise form of Crispr.
But Leonard points out that getting Crispr into other cells and organs is still a mystery. “The brain and lungs are hard to reach,” says Leonard. “If you think about the coming years, these are the areas where standard lipid nanoparticle technology may not work and you may need other systems.”
Where Crispr will go next depends on where researchers can send it.