Journal
MOLECULAR THERAPY
Volume 21, Issue 2, Pages 318-323Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2012.258
Keywords
-
Categories
Funding
- Support Program for Strategic Research Infrastructure from the Japanese Ministry of Education, Culture, Sports, Science and Technology
- Health, Labor, and Science Research Grants for Research on HIV/AIDS
- Research on Intractable Diseases from the Japanese Ministry of Health, Labor, and Welfare
- [20591155]
- [21591249]
- [21790920]
- Grants-in-Aid for Scientific Research [23659493, 24591430] Funding Source: KAKEN
Ask authors/readers for more resources
Neutralizing antibodies (NAbs) against adeno-associated viruses (AAVs) are known to interfere with AAV vector-mediated gene transfer by intravascular delivery. Evading the inhibitory effects of antibodies against AAV vectors is necessary for efficient transfer of therapeutic genes clinically. For this purpose, we tested the efficacy of saline flushing in order to avoid contact of vectors with NAbs present in blood. Direct injection of the AAV8 vector carrying the factor IX (FIX) gene into the portal vein of macaques using saline flushing achieved transgene-derived FIX expression (4.7 +/- 2.10-10.1 +/- 5.45% of normal human FIX concentration) in the presence of NAbs. Expression was as efficient as that (5.43 +/- 2.59-12.68 +/- 4.83%) in macaques lacking NAbs. We next tested the efficacy of saline flushing using less invasive balloon catheter-guided injection. This approach also resulted in efficient expression of transgene-derived FIX (2.5 +/- 1.06-9.0 +/- 2.37%) in the presence of NAbs (14-56x dilutions). NAbs at this range of titers reduced the efficiency of transduction in the macaque liver by 100-fold when the same vector was injected into mesenteric veins without balloon catheters. Our results suggest that portal vein-directed vector delivery strategies with flushing to remove blood are efficacious for minimizing the inhibitory effect of anti-AAV antibodies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available