The therapy itself, according to Lebwohl, may be a decent choice for those with amyloidosis, but the results are considerably more important. This is the first time gene editing has been demonstrated to work in people, which “opens up a whole new field of treatments for patients that weren’t previously available.”

Intellia Therapeutics is set to offer the world the first-in-human gene editing data, which will mark the beginning of a watershed moment in medical advancements for genetic diseases.

The interim findings for Intellia and Regeneron’s in vivo CRISPR/Cas9 genome editing candidate, NTLA-2001, in patients with transthyretin (ATTR) amyloidosis are in, and the results are promising. In individuals who got a larger dose of NTLA-2001, blood levels of transthyretin, a crucial biomarker for the illness, were decreased by 87%. This outcome outperformed standard-of-care treatment, which generally lowers transthyretin by 80%.

“It’s actually beyond what we expected, which is a wonderful thing,” said David Lebwohl, M.D., Intellia’s chief medical officer.

According to Lebwohl, the treatment itself might be a good choice for individuals with amyloidosis, but the results are far more significant. This is the first time gene editing has been shown to function in humans, which “opens up a whole new area of therapies for patients that wasn’t there.”

The expectation is that the benefits of NTLA-2001 will be long-lasting after a single treatment, despite the fact that the initial data is just approximately a month old. While this preliminary study does not show that the therapy has therapeutic effects, Lebwohl says that the decrease in serum levels is a recognized biomarker in ATTR amyloidosis that indicates a significant patient benefit.

NTLA-2001 works by delivering a two-part genome editing system to the liver through lipid nanoparticles.
The first component is a guide RNA that is unique to the disease-causing gene, and the second component is a messenger RNA— an advancement made famous by COVID-19— that encodes the Cas9 protein and performs precise editing.

According to Lebwohl, CRISPR/Cas9 treatments function similarly to vaccines. These medicines vary from gene therapies, some of which are currently FDA-approved, in that they do not transfer the gene-altering characteristics via a virus. Gene therapeutics, he added, fade off over time.

In this research, the gene editing treatment was sent to the liver, which is the source of the faulty transthyretin that builds up in the blood, but Lebwohl believes it may be taken further. Thanks to a donation from the Bill & Melinda Gates Foundation, Intellia is focusing on bone marrow delivery, which might lead to a therapy that can correct sickle cell anemia.

“The potential is to some degree unlimited,” he said. “Really it’s just using our imagination of how we can affect human disease more profoundly.”

“I’ve worked on some amazing drugs. This is even more amazing to have something that can profoundly change the patient’s life,” Lebwohl said.

Intellia partnered with Regeneron in 2016 to develop in vivo CRISPR/Cas9 gene editing technology. Regeneron noted in a statement that the research is exciting not only for patients but also for the whole scientific community working on gene-based therapies.

ATTR amyloidosis is a rare and deadly illness that affects people who are born with TTR gene abnormalities that cause the liver to generate aberrant, frequently misfolded TTR proteins. Damaged proteins, which in their normal state deliver thyroid hormones and vitamin A in the blood, accumulate in the body, creating a slew of issues with the neurological system, heart, and other organs.

Intellia’s initial focus is on the polyneuropathy subtype of the illness, which manifests as nerve damage. However, the company plans to enter the cardiomyopathy manifestation as well, which can lead to heart failure. According to Lebwohl, Intellia picked the polyneuropathy subtype to begin with since patients with cardiomyopathy tend to be very ill, making the therapy’s effects difficult to distinguish from the various problems observed with this kind of disease.

“Until now we really didn’t have any evidence that if you put CRISPR or any gene editing tool directly in the human body, it would be both effective as well as — as far as we can see from this study — safe,” said Kiran Musunuru, an American cardiologist who is a Professor of Medicine at the University of Pennsylvania Perelman School of Medicine. Musunuru researches the genetics and genomics of cardiovascular and metabolic diseases. “This is the first clinical trial that convincingly shows that yes, [in vivo] gene editing can work and can work very well.”


The study was published in the New England Journal of Medicine on June 26th, 2021.


Results. Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram.

Conclusions. In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051. opens in new tab.)