Format

Send to

Choose Destination
Mol Ther. 2016 Feb;24(2):276-286. doi: 10.1038/mt.2015.212. Epub 2015 Dec 7.

A Comprehensive Map of CNS Transduction by Eight Recombinant Adeno-associated Virus Serotypes Upon Cerebrospinal Fluid Administration in Pigs.

Author information

1
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
2
Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Bologna, Italy.
3
Shire, Discovery Biology and Translational Research, Lexington, Massachusetts, USA.
4
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Medical Genetics, Department of Translational Medicine, "FEDERICO II" University, Naples, Italy.
5
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.
6
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy. Electronic address: fraldi@tigem.it.

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.

PMID:
26639405
PMCID:
PMC4817820
DOI:
10.1038/mt.2015.212
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center