Crispr ingredients can’t naturally enter cells on their own, so Intellia uses a delivery system called lipid nanoparticles — essentially tiny fat bubbles — to deliver them. liver. In the Intellia trials, patients received a one-time intravenous infusion of these Crispr-rich nanoparticles into the veins of their arm. Since blood passes through the liver, lipid nanoparticles can easily travel from the blood there. In the liver, nanoparticles are taken up by cells called hepatocytes. Once inside these cells, the nanoparticles would break down and let Crispr proceed to edit the problematic gene.
In both diseases, an inherited mutation allows an unstable protein to run amok and cause damage. In hereditary angioedema, Intellia’s Crispr treatment is designed to eliminate KLKB1 genes in hepatocytes, reducing the production of the protein kallikrein. Too much kallikrein leads to overproduction of another protein, called bradykinin, which is responsible for recurrent, debilitating and potentially fatal episodes of swelling.
According to an Intellia Press Release, prior to receiving the Crispr infusion, the patient experienced one to seven swellings per month. During the 16-week observational period, the Crispr infusion reduced those attacks by an average of 91%.
In transthyretin amyloidosis, mutations in CHILD genes that cause the liver to produce abnormal versions of the protein transthyretin. These damaged proteins build up over time, causing serious complications in tissues including the heart, nerves, and digestive system. A disease that 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 be alive only two to six years.
Intellia’s Crispr processor is designed to be disabled CHILD genes and reduce the accumulation of pathogenic proteins it produces. Vaishali Sanchorawala, director of the Center for Amyloidosis at Boston University School of Medicine, says the reductions Intellia are reporting are exciting. “This has the potential to completely revolutionize outcomes for patients living with this disease,” says Sanchorawala.
One big question is whether the edits will be permanent. In some patients, Crispr shows promise for more than a year, says Leonard. But the liver cells eventually regenerate, and the scientists didn’t follow the patient long enough to know if the new cells extracted from the edited ones would also contain the gene editing. are not.
“What we do know is that when you edit a cell, it stays edited for life. There is no way to undo that. And if there’s revenue, the question is: Well, where do the new cells come from? In the case of the liver, it comes from other liver cells,” says Leonard. “We think that once you’ve got it in the upstream cell from which everything else follows, it’s forever.”
Scientists working on Crispr therapy in vivo have focused on the liver as an initial target because many genetic diseases are associated with it. And because fats like lipids are easily absorbed by the liver, scientists at Intellia and elsewhere have discovered that they can be used to deliver Crispr there.
Two other companies, Beam Therapeutics and Verve Therapeutics, are also using lipid nanoparticles to target the liver by gene editing. In July, Verve began testing a treatment for an inherited form of high cholesterol with base edit, a more precise form of Crispr.
But Leonard points out that getting Crispr to other cells and organs is still a puzzle. “Where it’s hard to get to is the brain and the lungs,” says Leonard. “When you think about the coming years, those are areas where standard lipid nanoparticle technology may not work and you may need other systems.”
Where Crispr goes next will depend on where the researchers can send it.