When Patrick Doherty learned he had inherited a lethal disease called transthyretin amyloidosis (ATTR), he enrolled in a trial using CRISPR to treat the condition. The treatment helped stop his symptoms, marking what experts are calling a breakthrough for the gene-editing technology.

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'It's [a] terrible prognosis'

About a year and a half ago, Doherty said, he began noticing feelings of pins and needles in his fingers and toes. He also noticed that his feet would sometimes get cold and that he easily ran out of breath when he walked his dog up and down hills.

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Doherty ultimately was diagnosed with ATTR—the same condition that had already killed his father. According to Julian Gillmore, a professor of medicine at University College London, ATTR is a largely inherited disease—although, in rare "wild-type" cases, it can be acquired—caused by mutations to the TTR gene. It affects about 50,000 people worldwide.

In people afflicted with the disease, the liver produces a misshapen version of the transthyretin protein. It builds up over time and eventually destroys vital tissue, such as the nerves in the heart, feet, and hands.

"It's [a] terrible prognosis," Doherty said. "This is a condition that deteriorates very rapidly. It's just dreadful."

An innovative trial

So when Doherty learned of a Phase 1 trial in which researchers sponsored by Intellia Therapeutics were using CRISPR gene-editing technology to treat ATTR, he quickly enrolled. "I jumped at the opportunity," he said.

For the treatment, doctors infused "billions" of lipid nanoparticles (LNPs) into patients' bloodstreams. Those LNPs were absorbed by the patients' livers, where they released the genetic instructions to create "armies of CRISPR gene-editors," "Shots" reports, which in turn targeted the affected TTR gene in liver cells to disable production of the disease-causing protein.

In a paper in the New England Journal of Medicine, researchers released early results from the clinical trial, which found the CRISPR treatment reduced the levels of the disease-causing protein by 52% in patients who received a low dose and by 87% in those receiving a high dose. There was no indication of adverse events or liver toxicity, MedCity News reports.

The results are similar to those produced by standard care for ATTR, which typically drives an 80% reduction in the disease-causing proteins. But that standard care is far more burdensome, requiring either an infusion every three weeks or a shot every week, while the CRISPR treatment appears to provide permanent changes with just a single treatment.

For Doherty's part, he said he feels "fantastic. It's just phenomenal."

What this means for the future of CRISPR

According to MedCity News, experts said the early results of this trial are a breakthrough for the CRISPR technology, as it's the first time a treatment driven by CRISPR has been infused directly into a patient and allowed to find its way to the correct cells. Previously, researchers have either had to harvest the targeted cells, edit them externally, and then re-infuse them back into the patients, or directly inject CRISPR to the target area—neither of which would work for this particular disease, STAT+ reports.

According to "Shots," researchers believe this new approach could ultimately enable treatment for other conditions and diseases in which harvesting cells or directly injecting CRISPR isn't feasible, such as Alzheimer's disease, heart disease, and more.

"This is the first example in which CRISPR-Cas9 is injected directly into the bloodstream—in other words, systemic administration—where we use it as a way to reach a tissue that's far away from the site of injection and very specifically use it to edit disease-causing genes," John Leonard, CEO of Intellia Therapeutics, said.

He added, "This is really opening a new era as we think about gene-editing, where we can begin to think about accessing all kinds of different tissue in the body via systemic administration."

Gillmore—who served as the national coordinating investigator for the Phase 1 trials—said the results not only appear to have "the potential to completely revolutionize the outcome for [ATTR] patients who have lived with this disease in their family for many generations," but also "provide proof of concept for a promising new therapeutic strategy."

Separately, Jennifer Doudna, from the University of California-Berkeley, who won a Nobel Prize for her help developing CRISPR and co-founded Intellia, said the trial represents "a major milestone," indicating that "we can overcome one of the biggest challenges with applying CRISPR clinically so far, which is being able to deliver it systemically and get it to the right place."

The key to this study is the use of LNPs with CRISPR, Daniel Anderson, a chemical engineer at the Massachusetts Institute of Technology and scientific co-founder of CRISPR Therapeutics, said.

"There's no question that LNPs are the hero here because without them, CRISPR is a very exciting technology but it would simply not be used in this fashion," Anderson said. "Now we've got an exciting genome editing early result, so I think it's fair to say LNPs are clearly here to stay, at least for a while." (Walrath, Boston Business Journal, 6/28; Vinluan, MedCity News, 6/28; Molteni, STAT+ [subscription required], 6/26; Stein, "Shots," NPR, 6/26).