• Julian D Gillmore, Ed Gane, Jorg Taubel, Justin Kao, Marianna Fontana, Michael L Maitland, Jessica Seitzer, Daniel O'Connell, Kathryn R Walsh, Kristy Wood, Jonathan Phillips, Yuanxin Xu, Adam Amaral, Adam P Boyd, Jeffrey E Cehelsky, Mark D McKee, Andrew Schiermeier, Olivier Harari, Andrew Murphy, Christos A Kyratsous, Brian Zambrowicz, Randy Soltys, David E Gutstein, John Leonard, Laura Sepp-Lorenzino, and David Lebwohl.
• From the National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital (J.D.G., M.F.) and Richmond Pharmacology, St. George's University of London (J.T.) - both in London; New Zealand Clinical Research (E.G.), University of Auckland (E.G.), and the Department of Neurology, Auckland City Hospital (J.K.) - all in Auckland, New Zealand; Intellia Therapeutics, Cambridge, MA (M.L.M., J.S., D.O., K.R.W., K.W., J.P., Y.X., A.A., A.P.B., J.E.C., M.D.M., A.S., J.L., L.S.-L., D.L.); and Regeneron Pharmaceuticals, Tarrytown, NY (O.H., A.M., C.A.K., B.Z., R.S., D.E.G.).
• N. Engl. J. Med. 2021 Aug 5; 385 (6): 493502493-502.

BackgroundTransthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR.MethodsAfter conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study.ResultsPreclinical 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.ConclusionsIn 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.).Copyright © 2021 Massachusetts Medical Society.

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