A small trial exploring what happens when patients were given a second infusion of an experimental CRISPR therapy suggests that it could be safe to readminister, opening the door to treating conditions in hard-to-reach parts of the body that might require more than one dose for maximum benefit.
In the three-person study, Intellia Therapeutics gave a second infusion of its gene editing therapy to transthyretin amyloidosis patients who got the lowest of three doses in an earlier study. The original treatment lowered levels of a blood protein, TTR, by 52%.
John Leonard“We probably under-dosed some patients,” CEO John Leonard told Endpoints News in an interview. “So we made the promise to patients that, if we find a dose that tends to be successful, we’ll make that available to them.”
At the Peripheral Nerve Society Annual Meeting in Montreal on Tuesday, the company reported that a second dose of the drug, dubbed NTLA-2001, lowered the protein levels by 90% more, resulting in a total 95% reduction that slightly exceeds the benefits that other individuals got from a single, higher dose.
While the study is small, the results are a best-case scenario that could create new options for how gene therapies could be administered and what to do about people who don’t generate a sufficient response, or whose response wanes.
Traditional gene therapies can’t be redosed because people develop immunity to the viral vectors used to deliver the gene into cells. While Intellia instead used lipid nanoparticles, which don’t have the immunity problems of viruses, CRISPR editing relies on a bacterial protein called Cas9 that some scientists have worried could have its own issues, either because of preexisting immunity to the protein, or immunity developed after a dose.
Intellia’s small study doesn’t prove that such reactions will never be a concern, but it’s an encouraging sign that they won’t be common. One person developed a mild infusion reaction, characterized by redness and a headache, but Intellia said that there were no changes in liver enzymes, platelets, or coagulation that would indicate a problem with the treatment.
“From a safety point of view, they are indistinguishable from everybody else. They did extremely well,” Leonard said.
Redosing a CRISPR treatment may seem counterintuitive, since the biggest promise of gene editing is the potential for one-time treatments that lead to lifelong cures. But those cures are contingent on editing enough of the broken or offending genes.
While editing rates are high in the liver, where lipid nanoparticles used to deliver the CRISPR machinery naturally congregate, getting enough of the treatment into the bone marrow, brain, lungs, muscles, and other organs remains a major challenge. Even with new nanoparticles designed with those organs in mind, a single treatment might not be enough to treat some conditions.
Of course, just because one lipid nanoparticle is safe to redose doesn’t mean that others will be, too. And the safety of redosing in patients who got a larger dose to begin with is unknown. But for Intellia and other companies trying to make therapies that can edit blood stem cells directly in the bone marrow, redosable nanoparticles could be the key to making the therapy work.
“Knowing that you can go back and get incremental editing may turn out to be very useful for blood disorders,” Leonard said. “That’s not our goal. Our goal would always be to do it one-and-done. But if two or three infusions is what it takes to get there, then a lipid nanoparticle is probably going to be a good way to accomplish that.”