Efficacy and safety of adeno-associated viral vectors based on serotype 8 and 9 vs. lentiviral vectors for hemophilia B gene therapy.
BACKGROUND
Adeno-associated viral (AAV) and lentiviral vectors are promising vectors for gene therapy for hemophilia because they are devoid of viral genes and have the potential for long-term gene expression.


OBJECTIVE
To compare the performance of different AAV serotypes (AAV8 and AAV9) vs. lentiviral vectors expressing factor (F) IX.


RESULTS
AAV-based and lentiviral vectors were generated that express FIX from the same hepatocyte-specific expression cassette. AAV9 transduced the liver as efficiently as AAV8 and resulted in supra-physiological FIX levels (3000-6000% of normal) stably correcting the bleeding diathesis. Surprisingly, AAV9 resulted in unprecedented and widespread cardiac gene transfer, which was more efficient than with AAV8. AAV8 and AAV9 were not associated with any proinflammatory cytokine induction, in accordance with their minimal interactions with innate immune effectors. In contrast, lentiviral transduction resulted in modest and stable FIX levels near the therapeutic threshold (1%) and triggered a rapid self-limiting proinflammatory response (interleukin-6), which probably reflected their ability to efficiently interact with the innate immune system.


CONCLUSIONS
AAV8 and 9 result in significantly higher FIX expression levels and have a reduced proinflammatory risk in comparison with lentiviral vectors. The unexpected cardiotropic properties of AAV9 have implications for gene therapy for heart disease.
Vandendriessche
T
T
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium.
Thorrez
L
L
Acosta-Sanchez
A
A
Petrus
I
I
Wang
L
L
Ma
L
L
DE Waele
L
L
Iwasaki
Y
Y
Gillijns
V
V
Wilson
J M
JM
Collen
D
D
Chuah
M K L
MK
D000818:Animals; D001760:Bleeding Time; D000229:Dependovirus / Q000145:classification / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D005164:Factor IX / Q000096:biosynthesis* / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000009:adverse effects / Q000187:drug effects; D006331:Heart Diseases / Q000628:therapy; D002836:Hemophilia B / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D016086:Lentivirus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D012703:Serotyping; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D042461:Vascular Endothelial Growth Factor A; D005164:Factor IX