Prediction of adeno-associated virus neutralizing antibody activity for clinical application.

Content Provider	Europe PMC
Author	Wang, Mei Crosby, Ashley Hastie, Eric Samulski, Jade J. McPhee, Scott Joshua, Grieger Samulski, R. Jude Li, Chengwen
Abstract	Patients with neutralizing antibodies (Nab) against adeno-associated virus (AAV) are usually excluded from treatment with AAV vectors. To develop a standard assay for detecting Nab inhibition activity, we systematically studied current AAV Nab assays in vitro and in vivo. Several factors were found that influence the Nab titers based on the in vitro assay, including: sera volume, AAV dose/cell, cell number and choice of transgenes. When the Nab titer assay was performed in vivo via intramuscular (IM) or systemic administration, a 4-fold increase in sensitivity for measurement of Nab titers was observed compared to an identical in vitro test. To better mimic the clinical setting, after passively transferring human Nabs into mice, blood was collected before systemic injection of AAV vector and used for Nab titer analysis in vitro or via IM injection. The results showed that AAV delivered via IM injection had a similar inhibition pattern to systemic administration. These studies indicate critical parameters necessary for optimizing Nab sensitivity and that an in vivo Nab assay is more sensitive than an in vitro assay for inclusion/exclusion criteria. The variables identified by this study may explain some of the compounding clinical data seen to date with respect to efficiency of AAV transduction in various Phase I clinical trials.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC4670282&blobtype=pdf
ISSN	09697128
Journal	Gene therapy [Gene Ther]
Volume Number	22
DOI	10.1038/gt.2015.69
PubMed Central reference number	PMC4670282
Issue Number	12
PubMed reference number	26125606
e-ISSN	14765462
Language	English
Publisher Date	2015-06-30
Access Restriction	Open
Rights License	Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
Subject Keyword	AAV gene therapy neutralizing antibody muscular injection systemic administration
Content Type	Text
Resource Type	Article
Subject	Genetics Molecular Biology Molecular Medicine