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In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels.
Rothgangl, Tanja; Dennis, Melissa K; Lin, Paulo J C; Oka, Rurika; Witzigmann, Dominik; Villiger, Lukas; Qi, Weihong; Hruzova, Martina; Kissling, Lucas; Lenggenhager, Daniela; Borrelli, Costanza; Egli, Sabina; Frey, Nina; Bakker, Noëlle; Walker, John A; Kadina, Anastasia P; Victorov, Denis V; Pacesa, Martin; Kreutzer, Susanne; Kontarakis, Zacharias; Moor, Andreas; Jinek, Martin; Weissman, Drew; Stoffel, Markus; van Boxtel, Ruben; Holden, Kevin; Pardi, Norbert; Thöny, Beat; Häberle, Johannes; Tam, Ying K; Semple, Sean C; Schwank, Gerald.
Afiliación
  • Rothgangl T; University of Zurich, Institute for Pharmacology and Toxicology, Zurich, Switzerland.
  • Dennis MK; Acuitas Therapeutics Inc., Vancouver, BC, Canada.
  • Lin PJC; Acuitas Therapeutics Inc., Vancouver, BC, Canada.
  • Oka R; Oncode Institute, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
  • Witzigmann D; University of Zurich, Institute for Pharmacology and Toxicology, Zurich, Switzerland.
  • Villiger L; University of Zurich, Institute for Pharmacology and Toxicology, Zurich, Switzerland.
  • Qi W; Functional Genomics Center Zurich, ETH Zurich/University of Zurich, Zurich, Switzerland.
  • Hruzova M; Department of Biology, Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
  • Kissling L; University of Zurich, Institute for Pharmacology and Toxicology, Zurich, Switzerland.
  • Lenggenhager D; Department of Pathology and Molecular Pathology, University Hospital and University of Zurich, Zurich, Switzerland.
  • Borrelli C; Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland.
  • Egli S; University of Zurich, Institute for Pharmacology and Toxicology, Zurich, Switzerland.
  • Frey N; Department of Biology, Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
  • Bakker N; University of Zurich, Institute for Pharmacology and Toxicology, Zurich, Switzerland.
  • Walker JA; Synthego Corporation, Redwood City, CA, USA.
  • Kadina AP; Synthego Corporation, Redwood City, CA, USA.
  • Victorov DV; Synthego Corporation, Redwood City, CA, USA.
  • Pacesa M; Department of Biochemistry, University of Zurich, Zurich, Switzerland.
  • Kreutzer S; Functional Genomics Center Zurich, ETH Zurich/University of Zurich, Zurich, Switzerland.
  • Kontarakis Z; Genome Engineering and Measurement Laboratory, ETH Zurich, Zurich, Switzerland.
  • Moor A; Functional Genomics Center Zurich, ETH Zurich/University of Zurich, Zurich, Switzerland.
  • Jinek M; Genome Engineering and Measurement Laboratory, ETH Zurich, Zurich, Switzerland.
  • Weissman D; Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland.
  • Stoffel M; Department of Biochemistry, University of Zurich, Zurich, Switzerland.
  • van Boxtel R; Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Holden K; Department of Biology, Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
  • Pardi N; Oncode Institute, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
  • Thöny B; Synthego Corporation, Redwood City, CA, USA.
  • Häberle J; Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Tam YK; Division of Metabolism and Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
  • Semple SC; Zurich Center for Integrative Human Physiology, Zurich, Switzerland.
  • Schwank G; Neuroscience Center Zurich, Zurich, Switzerland.
Nat Biotechnol ; 39(8): 949-957, 2021 08.
Article en En | MEDLINE | ID: mdl-34012094
Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle-based delivery of mRNA encoding an ABE and a single-guide RNA targeting PCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Adenina / Proproteína Convertasa 9 / Edición Génica / LDL-Colesterol Límite: Animals Idioma: En Revista: Nat Biotechnol Asunto de la revista: BIOTECNOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Suiza

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Adenina / Proproteína Convertasa 9 / Edición Génica / LDL-Colesterol Límite: Animals Idioma: En Revista: Nat Biotechnol Asunto de la revista: BIOTECNOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Suiza