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Multimodal imaging of capsid and cargo reveals differential brain targeting and liver detargeting of systemically-administered AAVs.
Seo, Jai Woong; Ajenjo, Javier; Wu, Bo; Robinson, Elise; Raie, Marina Nura; Wang, James; Tumbale, Spencer K; Buccino, Pablo; Anders, David Alexander; Shen, Bin; Habte, Frezghi G; Beinat, Corinne; James, Michelle L; Reyes, Samantha Taylor; Ravindra Kumar, Sripriya; Miles, Timothy F; Lee, Jason T; Gradinaru, Viviana; Ferrara, Katherine W.
Afiliación
  • Seo JW; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Ajenjo J; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Wu B; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Robinson E; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Raie MN; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Wang J; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Tumbale SK; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Buccino P; Stanford Cyclotron & Radiochemistry Facility (CRF), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Anders DA; Stanford Cyclotron & Radiochemistry Facility (CRF), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Shen B; Stanford Cyclotron & Radiochemistry Facility (CRF), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Habte FG; Stanford Center for Innovation in In vivo Imaging (SCi3), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Beinat C; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • James ML; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Reyes ST; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Ravindra Kumar S; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
  • Miles TF; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
  • Lee JT; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Gradinaru V; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
  • Ferrara KW; Molecular Imaging Program at Stanford (MIPS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA. Electronic address: kwferrar@stanford.edu.
Biomaterials ; 288: 121701, 2022 09.
Article en En | MEDLINE | ID: mdl-35985893
ABSTRACT
The development of gene delivery vehicles with high organ specificity when administered systemically is a critical goal for gene therapy. We combine optical and positron emission tomography (PET) imaging of 1) reporter genes and 2) capsid tags to assess the temporal and spatial distribution and transduction of adeno-associated viruses (AAVs). AAV9 and two engineered AAV vectors (PHP.eB and CAP-B10) that are noteworthy for maximizing blood-brain barrier transport were compared. CAP-B10 shares a modification in the 588 loop with PHP.eB, but also has a modification in the 455 loop, added with the goal of reducing off-target transduction. PET and optical imaging revealed that the additional modifications retained brain receptor affinity. In the liver, the accumulation of AAV9 and the engineered AAV capsids was similar (∼15% of the injected dose per cc and not significantly different between capsids at 21 h). However, the engineered capsids were primarily internalized by Kupffer cells rather than hepatocytes, and liver transduction was greatly reduced. PET reporter gene imaging after engineered AAV systemic injection provided a non-invasive method to monitor AAV-mediated protein expression over time. Through comparison with capsid tagging, differences between brain localization and transduction were revealed. In summary, AAV capsids bearing imaging tags and reporter gene payloads create a unique and powerful platform to assay the pharmacokinetics, cellular specificity and protein expression kinetics of AAV vectors in vivo, a key enabler for the field of gene therapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cápside / Dependovirus Idioma: En Revista: Biomaterials Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cápside / Dependovirus Idioma: En Revista: Biomaterials Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos