Your browser doesn't support javascript.
loading
CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.
Gillmore, Julian D; Gane, Ed; Taubel, Jorg; Kao, Justin; Fontana, Marianna; Maitland, Michael L; Seitzer, Jessica; O'Connell, Daniel; Walsh, Kathryn R; Wood, Kristy; Phillips, Jonathan; Xu, Yuanxin; Amaral, Adam; Boyd, Adam P; Cehelsky, Jeffrey E; McKee, Mark D; Schiermeier, Andrew; Harari, Olivier; Murphy, Andrew; Kyratsous, Christos A; Zambrowicz, Brian; Soltys, Randy; Gutstein, David E; Leonard, John; Sepp-Lorenzino, Laura; Lebwohl, David.
Afiliação
  • Gillmore JD; 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 N
  • Gane E; 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 N
  • Taubel J; 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 N
  • Kao J; 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 N
  • Fontana M; 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 N
  • Maitland ML; 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 N
  • Seitzer J; 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 N
  • O'Connell D; 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 N
  • Walsh KR; 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 N
  • Wood K; 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 N
  • Phillips J; 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 N
  • Xu Y; 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 N
  • Amaral A; 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 N
  • Boyd AP; 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 N
  • Cehelsky JE; 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 N
  • McKee MD; 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 N
  • Schiermeier A; 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 N
  • Harari O; 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 N
  • Murphy A; 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 N
  • Kyratsous CA; 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 N
  • Zambrowicz B; 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 N
  • Soltys R; 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 N
  • Gutstein DE; 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 N
  • Leonard J; 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 N
  • Sepp-Lorenzino L; 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 N
  • Lebwohl D; 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 N
N Engl J Med ; 385(6): 493-502, 2021 08 05.
Article em En | MEDLINE | ID: mdl-34215024
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.).
Assuntos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pré-Albumina / RNA Guia de Cinetoplastídeos / Neuropatias Amiloides Familiares / Nanopartículas / Sistemas CRISPR-Cas / Edição de Genes / Lipossomos Tipo de estudo: Clinical_trials Limite: Female / Humans / Male / Middle aged Idioma: En Revista: N Engl J Med Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pré-Albumina / RNA Guia de Cinetoplastídeos / Neuropatias Amiloides Familiares / Nanopartículas / Sistemas CRISPR-Cas / Edição de Genes / Lipossomos Tipo de estudo: Clinical_trials Limite: Female / Humans / Male / Middle aged Idioma: En Revista: N Engl J Med Ano de publicação: 2021 Tipo de documento: Article