Preexisting immunity and low expression in primates highlight translational challenges for liver-directed AAV8-mediated gene therapy.
Liver-directed gene therapy with adeno-associated virus (AAV) vectors effectively treats mouse models of lysosomal storage diseases (LSDs). We asked whether these results were likely to translate to patients. To understand to what extent preexisting anti-AAV8 antibodies could impede AAV8-mediated liver transduction in primates, commonly preexposed to AAV, we quantified the effects of preexisting antibodies on liver transduction and subsequent transgene expression in mouse and nonhuman primate (NHP) models. Using the highest viral dose previously reported in a clinical trial, passive transfer of NHP sera containing relatively low anti-AAV8 titers into mice blocked liver transduction, which could be partially overcome by increasing vector dose tenfold. Based on this and a survey of anti-AAV8 titers in 112 humans, we predict that high-dose systemic gene therapy would successfully transduce liver in >50% of human patients. However, although high-dose AAV8 administration to mice and monkeys with equivalent anti-AAV8 titers led to comparable liver vector copy numbers, the resulting transgene expression in primates was ~1.5-logs lower than mice. This suggests vector fate differs in these species and that strategies focused solely on overcoming preexisting vector-specific antibodies may be insufficient to achieve clinically meaningful expression levels of LSD genes using a liver-directed gene therapy approach in patients.
Hurlbut
Gregory D
GD
Genzyme Corporation, Framingham, Massachusetts, USA.
Ziegler
Robin J
RJ
Nietupski
Jennifer B
JB
Foley
Joseph W
JW
Woodworth
Lisa A
LA
Meyers
Elizabeth
E
Bercury
Scott D
SD
Pande
Nilesh N
NN
Souza
David W
DW
Bree
Mark P
MP
Lukason
Michael J
MJ
Marshall
John
J
Cheng
Seng H
SH
Scheule
Ronald K
RK
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D015153:Blotting, Western; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006367:HeLa Cells; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010956:Plasmapheresis; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes / Q000502:physiology*; D000519:alpha-Galactosidase / Q000097:blood* / Q000235:genetics
D057134:Antibodies, Neutralizing; D012333:RNA, Messenger; D000519:alpha-Galactosidase