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Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins.
Banskota, Samagya; Raguram, Aditya; Suh, Susie; Du, Samuel W; Davis, Jessie R; Choi, Elliot H; Wang, Xiao; Nielsen, Sarah C; Newby, Gregory A; Randolph, Peyton B; Osborn, Mark J; Musunuru, Kiran; Palczewski, Krzysztof; Liu, David R.
Afiliación
  • Banskota S; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
  • Raguram A; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
  • Suh S; Gavin Herbert Eye Institute, Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, CA, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.
  • Du SW; Gavin Herbert Eye Institute, Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
  • Davis JR; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
  • Choi EH; Gavin Herbert Eye Institute, Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, CA, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.
  • Wang X; Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School o
  • Nielsen SC; Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapy, University of Minnesota, Minneapolis, MN, USA.
  • Newby GA; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
  • Randolph PB; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
  • Osborn MJ; Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapy, University of Minnesota, Minneapolis, MN, USA.
  • Musunuru K; Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School o
  • Palczewski K; Gavin Herbert Eye Institute, Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, CA, USA; Department of Chemistry, University of California, Irvine, CA, USA; Depar
  • Liu DR; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA. Electronic address: dr
Cell ; 185(2): 250-265.e16, 2022 01 20.
Article en En | MEDLINE | ID: mdl-35021064
ABSTRACT
Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient base editing in several primary mouse and human cell types. Using different glycoproteins in eVLPs alters their cellular tropism. Single injections of eVLPs into mice support therapeutic levels of base editing in multiple tissues, reducing serum Pcsk9 levels 78% following 63% liver editing, and partially restoring visual function in a mouse model of genetic blindness. In vitro and in vivo off-target editing from eVLPs was virtually undetected, an improvement over AAV or plasmid delivery. These results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and nonviral delivery.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Virión / Proteínas / Ingeniería Genética / Sistemas de Liberación de Medicamentos Límite: Animals / Humans Idioma: En Revista: Cell Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Virión / Proteínas / Ingeniería Genética / Sistemas de Liberación de Medicamentos Límite: Animals / Humans Idioma: En Revista: Cell Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos