title: A Comprehensive Map of CNS Transduction by Eight Recombinant Adeno-associated Virus Serotypes Upon Cerebrospinal Fluid Administration in Pigs.
abstract: Cerebrospinal fluid administration of recombinant adeno-associated viral (rAAV) vectors has been demonstrated to be effective in delivering therapeutic genes to the central nervous system (CNS) in different disease animal models. However, a quantitative and qualitative analysis of transduction patterns of the most promising rAAV serotypes for brain targeting in large animal models is missing. Here, we characterize distribution, transduction efficiency, and cellular targeting of rAAV serotypes 1, 2, 5, 7, 9, rh.10, rh.39, and rh.43 delivered into the cisterna magna of wild-type pigs. rAAV9 showed the highest transduction efficiency and the widest distribution capability among the vectors tested. Moreover, rAAV9 robustly transduced both glia and neurons, including the motor neurons of the spinal cord. Relevant cell transduction specificity of the glia was observed after rAAV1 and rAAV7 delivery. rAAV7 also displayed a specific tropism to Purkinje cells. Evaluation of biochemical and hematological markers suggested that all rAAV serotypes tested were well tolerated. This study provides a comprehensive CNS transduction map in a useful preclinical large animal model enabling the selection of potentially clinically transferable rAAV serotypes based on disease specificity. Therefore, our data are instrumental for the clinical evaluation of these rAAV vectors in human neurodegenerative diseases.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Nicolina Cristina
authors.initials: NC
authors.lastname: Sorrentino
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Maffia
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Strollo
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cacace
authors.affiliation: Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Bologna, Italy.
authors.forename: Noemi
authors.initials: N
authors.lastname: Romagnoli
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Manfredi
authors.affiliation: Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Bologna, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ventrella
authors.affiliation: Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Bologna, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dondi
authors.affiliation: Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Barone
authors.affiliation: Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Bologna, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Giunti
authors.affiliation: Shire, Discovery Biology and Translational Research, Lexington, Massachusetts, USA.
authors.forename: Anne-Renee
authors.initials: AR
authors.lastname: Graham
authors.affiliation: Shire, Discovery Biology and Translational Research, Lexington, Massachusetts, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Shire, Discovery Biology and Translational Research, Lexington, Massachusetts, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Kalled
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Medical Genetics, Department of Translational Medicine, "FEDERICO II" University, Naples, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
authors.affiliation: Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Bologna, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bacci
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Medical Genetics, Department of Translational Medicine, "FEDERICO II" University, Naples, Italy. Electronic address: surace@tigem.it.
authors.forename: Enrico Maria
authors.initials: EM
authors.lastname: Surace
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy. Electronic address: fraldi@tigem.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fraldi
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000134:cerebrospinal fluid*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009928:Organ Specificity; D065288:Serogroup; D013552:Swine; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D049452:Green Fluorescent Proteins