CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis | oneAMYLOIDOSISvoice
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CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

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source: The New England Journal of Medicine

year: 2021

authors: 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

summary/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. 

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 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.

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. 

organization: National Amyloidosis Centre, UCL, UK; Royal Free Hospital and Richmond Pharmacology, UK ; St. George’s University of London, UK; New Zealand Clinical Research, New Zealand ; University of Auckland, New Zealand ; Auckland City Hospital, New Zealand; Intellia Therapeutics, USA; Regeneron Pharmaceuticals, New York

DOI: 10.1056/NEJMoa2107454

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