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An intravenous CRISPR infusion lowered levels of a disease-causing protein in vivo for the first time in humans, interim findings from a showed.

At day 28, mean reduction in serum transthyretin (TTR) was 87% in three people with hereditary transthyretin (ATTR) amyloidosis with polyneuropathy who had received a single 0.3 mg/kg dose of NTLA-2001, a CRISPR-Cas9 treatment, reported Julian Gillmore, MD, PhD, of University College London in England, and co-authors, in .

CRISPR-Cas9, a scissors-like tool that can cut and edit DNA, aimed to inactivate the TTR gene in liver cells to prevent misfolded TTR protein from being produced. The liver makes more than 99% of all circulating TTR.

"This is the first successful demonstration of therapeutic gene editing within patients' bodies, making it a watershed moment in modern medicine," said Kiran Musunuru, MD, PhD, MPH, director of the Genetic and Epigenetic Origins of Disease Program at the University of Pennsylvania in Philadelphia, who wasn't involved with the study.

"The investigators used lipid nanoparticle technology -- the same technology used in COVID-19 mRNA vaccines -- to deliver CRISPR into the liver, with the goal of turning down a gene responsible for hereditary ATTR amyloidosis," Musunuru told 名媛直播.

"What was astonishing about this first-in-human study is not just that the treatment worked, but that it worked extremely well in patients, in one case turning off the disease gene close to 100%. It's like launching a rocket ship in the hope of just getting into orbit, but making it all the way to the moon on the first try."

In other studies, researchers have removed blood stem cells from people with sickle cell anemia and beta-thalassemia, edited them with CRISPR, and infused them back into patients. A subretinal injection also has delivered CRISPR in a trial of people with inherited blindness.

The NTLA-2001 findings, however, are the "first-ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous infusion of CRISPR," noted John Leonard, MD, president and CEO of Intellia Therapeutics, which co-sponsored the trial with Regeneron Pharmaceuticals.

"Solving the challenge of targeted delivery of CRISPR-Cas9 to the liver, as we have with NTLA-2001, also unlocks the door to treating a wide array of other genetic diseases with our modular platform, and we intend to move quickly to advance and expand our pipeline," Leonard said .

NTLA-2001 is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system. It consists of a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR.

The ongoing phase I study looked at safety and pharmacodynamic effects of single doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy in England and New Zealand. Three people received 0.1 mg/kg and three people received 0.3 mg/kg. Serum TTR levels were measured at baseline and day 28, the time at which the drug effect reached its permanent nadir in preclinical studies.

Participants were 46 to 64 years old, and four were men. Body weight ranged from 70 to 90 kg. Three patients had a p.T80A mutation, two a p.S97Y mutation, and one a p.H110D mutation. Three patients received no prior therapy; three previously had received diflunisal.

Treatment with NTLA-2001 led to dose-dependent reductions in serum TTR. At day 28, mean serum TTR levels declined by 52% (range, 47% to 56%) in the 0.1 mg/kg group and by 87% (range, 80% to 96%) in the 0.3 mg/kg group.

At both dose levels, NTLA-2001 appeared to be well-tolerated with no serious adverse events and no liver findings.

Hereditary ATTR amyloidosis is a rare, rapidly progressive disease caused by a mutation in the TTR gene that results in the buildup of misfolded transthyretin and leads to amyloid deposits in the heart, gastrointestinal tract, and peripheral nerves. Life expectancy is about 3 to 15 years after the onset of neuropathy.

Two treatments to treat hereditary ATTR amyloidosis nerve pain won FDA approval in 2018: patisiran (Onpattro), an RNA interference drug that requires an intravenous infusion every 3 weeks, and inotersen (Tegsedi), an RNA-targeting drug that reduces the production of TTR protein through weekly subcutaneous injection. Both drugs achieved in clinical trials; patisiran showed a mean reduction of 81% and inotersen lowered serum concentration by 71%.

The clinical implications of the NTLA-2001 study could be profound, noted Joel Buxbaum, MD, of Scripps Research Institute in La Jolla, California, who wasn't involved with the study. "If, as the authors surmise, the effect is permanent, and without off-target effects when studied in a much larger patient population, it would be a significant improvement [over] current therapies for this class of disorders, at least with respect to frequency of therapy," he said.

"However, all that depends on the clinical effect of long-term suppression of hepatic TTR synthesis," Buxbaum told 名媛直播. "In the published studies of the various currently available ATTR therapeutics, approximately one-third of subjects have little or no clinical response, regardless of the degree of suppression of circulating protein levels, suggesting that while diminishing the supply side for TTR aggregation is likely to be necessary for clinical responsiveness, it may not be sufficient for optimal or profound therapeutic efficacy."

The NTLA-2001 phase I trial will enroll up to 38 adults, with a single-ascending dose phase followed by a dose-expansion phase that will include clinical measures of neurologic function, Intellia said. After phase I studies are complete, the company plans to move to pivotal studies for both polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis.

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