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A comprehensive study of a 29-capsid AAV library in a non-human primate central nervous system.
Kondratov, Oleksandr; Kondratova, Liudmyla; Mandel, Ronald J; Coleman, Kirsten; Savage, Michael A; Gray-Edwards, Heather L; Ness, Timothy J; Rodriguez-Lebron, Edgar; Bell, Robert D; Rabinowitz, Joseph; Gamlin, Paul D; Zolotukhin, Sergei.
Afiliación
  • Kondratov O; Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA. Electronic address: o.g.kondratov@ufl.edu.
  • Kondratova L; Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
  • Mandel RJ; Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610, USA.
  • Coleman K; Powell Gene Therapy Center University of Florida College of Medicine, Gainesville, FL 32610, USA.
  • Savage MA; Department of Ophthalmology and Visual Sciences, University of Alabama, Birmingham, AL 35294, USA.
  • Gray-Edwards HL; Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
  • Ness TJ; Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Rodriguez-Lebron E; Lacerta Therapeutics Inc., Alachua, FL 32615, USA.
  • Bell RD; Neuroscience Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
  • Rabinowitz J; Neuroscience Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
  • Gamlin PD; Department of Ophthalmology and Visual Sciences, University of Alabama, Birmingham, AL 35294, USA.
  • Zolotukhin S; Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA. Electronic address: szlt@ufl.edu.
Mol Ther ; 29(9): 2806-2820, 2021 09 01.
Article en En | MEDLINE | ID: mdl-34298128
Non-human primates (NHPs) are a preferred animal model for optimizing adeno-associated virus (AAV)-mediated CNS gene delivery protocols before clinical trials. In spite of its inherent appeal, it is challenging to compare different serotypes, delivery routes, and disease indications in a well-powered, comprehensive, multigroup NHP experiment. Here, a multiplex barcode recombinant AAV (rAAV) vector-tracing strategy has been applied to a systemic analysis of 29 distinct, wild-type (WT), AAV natural isolates and engineered capsids in the CNS of eight macaques. The report describes distribution of each capsid in 15 areas of the macaques' CNS after intraparenchymal (putamen) injection, or cerebrospinal fluid (CSF)-mediated administration routes (intracisternal, intrathecal, or intracerebroventricular). To trace the vector biodistribution (viral DNA) and targeted tissues transduction (viral mRNA) of each capsid in each of the analyzed CNS areas, quantitative next-generation sequencing analysis, assisted by the digital-droplet PCR technology, was used. The report describes the most efficient AAV capsid variants targeting specific CNS areas after each route of administration using the direct side-by-side comparison of WT AAV isolates and a new generation of rationally designed capsids. The newly developed bioinformatics and visualization algorithms, applicable to the comparative analysis of several mammalian brain models, have been developed and made available in the public domain.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Nervioso Central / Dependovirus / Proteínas de la Cápside / Vectores Genéticos Tipo de estudio: Guideline Límite: Animals Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Nervioso Central / Dependovirus / Proteínas de la Cápside / Vectores Genéticos Tipo de estudio: Guideline Límite: Animals Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos