• DOI:10.1056/NEJMoa2107454
• Corpus ID: 235722446

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.

@article{Gillmore2021CRISPRCas9IV,
  title={CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.},
  author={Julian D. Gillmore and E. H. Gane and Jorg Taubel and Justin C. Kao and Marianna Fontana and Michael L. Maitland and Jessica Seitzer and Daniel O’Connell and Kathryn R Walsh and Kristy Wood and Jonathan Phillips and Yuanxin Xu and Adam Amaral and Adam P. Boyd and Jeffrey E Cehelsky and Mark McKee and Andrew Schiermeier and Olivier A. Harari and Andrew Murphy and Christos A. Kyratsous and Brian Zambrowicz and Randy Soltys and David E. Gutstein and John Leonard and Laura Sepp-Lorenzino and David Lebwohl},
  journal={The New England journal of medicine},
  year={2021}
}

• J. Gillmore, E. Gane, +23 authors D. Lebwohl
• Published 26 June 2021
• Medicine, Biology
• The New England journal of medicine

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.).