“I went to Fyodor and said, ‘Hey, we’re getting all these great results in the clinic with CRISPR, but why hasn’t it scaled?” says Hu. Part of the reason is that most gene-editing companies are chasing the same few conditions, such as sickle-cell, where (as luck would have it) a single edit works for all patients. But that leaves around 400 million people who have 7,000 other inherited conditions without much hope to get their DNA fixed, Urnov estimated in his editorial.
Then, last May, came the dramatic demonstration of the first fully “personalized” gene-editing treatment. A team in Philadelphia, assisted by Urnov and others, succeeded in correcting the DNA of a baby, named KJ Muldoon, who had an entirely unique mutation that caused a metabolic disease. Though it didn’t target PKU, the project showed that gene editing could theoretically fix some inherited diseases “on demand.”
It also underscored a big problem. Treating a single child required a large team and cost millions in time, effort, and materials—all to create a drug that would never be used again.
That’s exactly the sort of situation the new “umbrella” trials are supposed to address. Kiran Musunuru, who co-led the team at the University of Pennsylvania, says he’s been in discussions with the FDA to open a study of bespoke gene editors this year focusing on diseases of the type Baby KJ had, called urea cycle disorders. Each time a new patient appears, he says, they’ll try to quickly put together a variant of their gene-editing drug that’s tuned to fix that child’s particular genetic problem.
Musunuru, who isn’t involved with Aurora, does not think the company’s plans for PKU count as fully personalized editors. “These corporate PKU efforts have nothing whatsoever to do with Baby KJ,” he says. He says his center continues to focus on mutations “so ultra-rare that we don’t see any scenario where a for-profit gene-editing company would find that indication to be commercially viable.”
Instead, what’s occurring in PKU, says Musunuru, is that researchers have realized they can assemble “a bunch” of the most frequent mutations “into a large enough group of patients to make a platform PKU therapy commercially viable.”
While that would still leave out many patients with extra-rare gene errors, Musunuru says any gene-editing treatment at all would still be “a big improvement over the status quo, which is zero genetic therapies for PKU.”