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Direct interaction of human serum proteins with AAV virions to enhance AAV transduction: immediate impact on clinical applications

Gene Therapy volume 24, pages 49–59 (2017)Cite this article

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Abstract

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.

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Acknowledgements

We are grateful to Xiaojing Chen and Karen Hogan for their excellent technical assistance. We acknowledge the UNC Biomedical Research Imaging Center (BRIC) Small Animal Imaging (SAI) facility for assistance of mouse imaging. This work was supported by National Institutes of Health Grants R01DK084033 and R01AI117408 (to CL and RJS), R01HL125749 (to CL), P01HL112761 and R01AI072176 (to RJS), P30-CA016086-35-37 and U54-CA151652-01-04 (to the BRIC SAI facility) and a research grant from Asklepios BioPharmaceutical (to CL). This research is based in part on work conducted using the UNC Michael Hooker Proteomics Center, which is supported in part by the NIH-NCI Grant Number CA016086 to the Lineberger Comprehensive Cancer Center.

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Authors and Affiliations

  1. Stem Cell Transplantation Center, Institute of Hematology, Chinese Academy of Medical Sciences, Tianjin, China

    M Wang

  2. Gene Therapy Center, University of North Carolina at Chapel Hill,

    M Wang, J Sun, A Crosby, K Woodard, M L Hirsch, R J Samulski & C Li

  3. Chapel Hill, NC, USA

    M Wang, J Sun, A Crosby, K Woodard, M L Hirsch, R J Samulski & C Li

  4. Department of Ophthalmology, University of North Carolina at Chapel Hill,

    M L Hirsch

  5. Chapel Hill, NC, USA

    M L Hirsch

  6. Department of Pharmacology, University of North Carolina at Chapel Hill,

    R J Samulski

  7. Chapel Hill, NC, USA

    R J Samulski

  8. Department of Pediatrics, University of North Carolina at Chapel Hill,

    C Li

  9. Chapel Hill, NC, USA

    C Li

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Correspondence to R J Samulski or C Li.

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Competing interests

R Jude Samulski is the founder and a shareholder at Asklepios BioPharmaceutical. He receives research support through the University of North Carolina from Asklepios BioPharmaceutical. He holds patents that have been licensed by UNC to Asklepios Biopharmaceutical, for which he receives royalties. He has consulted for Baxter Healthcare and has received payment for speaking. All other authors declare no conflict of interest.

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Wang, M., Sun, J., Crosby, A. et al. Direct interaction of human serum proteins with AAV virions to enhance AAV transduction: immediate impact on clinical applications. Gene Ther 24, 49–59 (2017). https://doi.org/10.1038/gt.2016.75

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