Direct interaction of human serum proteins with AAV virions to enhance AAV transduction: immediate impact on clinical applications.
Recent hemophilia B clinical trials using adeno-associated virus (AAV) gene delivery have demonstrated much lower coagulation factor IX (FIX) production in patients compared with the high levels observed in animal models and AAV capsid-specific cytotoxic T lymphocyte response elicited at high doses of AAV vectors. These results emphasize the necessity to explore effective approaches for enhancement of AAV transduction. Initially, we found that incubation of all AAV vectors with human serum enhanced AAV transduction. Complementary analytical experiments demonstrated that human serum albumin (HSA) directly interacted with the AAV capsid and augmented AAV transduction. The enhanced transduction was observed with clinical grade HSA. Mechanistic studies suggest that HSA increases AAV binding to target cells, and that the interaction of HSA with AAV does not interfere with the AAV infection pathway. Importantly, HSA incubation during vector dialysis also increased transduction. Finally, HSA enhancement of AAV transduction in a model of hemophilia B displayed greater than a fivefold increase in vector-derived circulating FIX, which improved the bleeding phenotype correction. In conclusion, incubation of HSA with AAV vectors supports a universal augmentation of AAV transduction and, more importantly, this approach can be immediately transitioned to the clinic for the treatment of hemophilia and other diseases.
Stem Cell Transplantation Center, Institute of Hematology, Chinese Academy of Medical Sciences, Tianjin, China.|Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
M
M
Wang
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
J
J
Sun
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
A
A
Crosby
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
K
K
Woodard
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
M L
ML
Hirsch
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
R J
RJ
Samulski
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
C
C
Li
D000818:Animals; D002213:Capsid / Q000378:metabolism*; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D057809:HEK293 Cells; D002836:Hemophilia B / Q000628:therapy*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*
D012709:Serum Albumin