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CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

Gillmore, JD; Gane, E; Taubel, J; Kao, J; Fontana, M; Maitland, ML; Seitzer, J; ... Lebwohl, D; + view all (2021) CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. New England Journal of Medicine , 385 pp. 493-502. 10.1056/NEJMoa2107454. Green open access

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Abstract

BACKGROUND: Transthyretin 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. METHODS: After 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. 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.)

Type: Article
Title: CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1056/NEJMoa2107454
Publisher version: https://doi.org/10.1056/NEJMoa2107454
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Medicine, General & Internal, General & Internal Medicine, DNA, POLYNEUROPATHY, PATISIRAN, CLEAVAGE, THERAPY, SAFETY
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10133469
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