Intramuscular injection of AAV8 in mice and macaques is associated with substantial hepatic targeting and transgene expression

Intramuscular (IM) administration of adeno-associated viral (AAV) vectors has entered the early stages of clinical development with some success, including the first approved gene therapy product in the West called Glybera. In preparation for broader clinical development of IM AAV vector gene therap...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2014-11, Vol.9 (11), p.e112268-e112268
Main Authors: Greig, Jenny A, Peng, Hui, Ohlstein, Jason, Medina-Jaszek, C Angelica, Ahonkhai, Omua, Mentzinger, Anne, Grant, Rebecca L, Roy, Soumitra, Chen, Shu-Jen, Bell, Peter, Tretiakova, Anna P, Wilson, James M
Format: Article
Language:English
Subjects:
Animals
Biology and Life Sciences
Clinical trials
Dependovirus - genetics
Developmental stages
Drug dosages
Expression vectors
Gene Expression
Gene therapy
Gene Transfer Techniques
Genetic Vectors - administration & dosage
Hemophilia
HIV
Human immunodeficiency virus
Immunoglobulins
Injection
Injections, Intramuscular
Kinases
Laboratories
Liver
Liver - metabolism
Macaca mulatta
Male
Medicine
Medicine and health sciences
Mice
MicroRNAs
MicroRNAs - metabolism
miRNA
Musculoskeletal system
Organ Specificity
Pathology
Ribonucleic acid
RNA
Transgenes
Vectors (Biology)
Viruses
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Intramuscular (IM) administration of adeno-associated viral (AAV) vectors has entered the early stages of clinical development with some success, including the first approved gene therapy product in the West called Glybera. In preparation for broader clinical development of IM AAV vector gene therapy, we conducted detailed pre-clinical studies in mice and macaques evaluating aspects of delivery that could affect performance. We found that following IM administration of AAV8 vectors in mice, a portion of the vector reached the liver and hepatic gene expression contributed significantly to total expression of secreted transgenes. The contribution from liver could be controlled by altering injection volume and by the use of traditional (promoter) and non-traditional (tissue-specific microRNA target sites) expression control elements. Hepatic distribution of vector following IM injection was also noted in rhesus macaques. These pre-clinical data on AAV delivery should inform safe and efficient development of future AAV products.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0112268