PhP.B Enhanced Adeno-Associated Virus Mediated-Expression Following Systemic Delivery or Direct Brain Administration

Frontiers in Bioengineering and Biotechnology, vol. 9, pp. 679483

Abstract

Of the adeno-associated viruses (AAVs), AAV9 is known for its capability to cross the blood-brain barrier (BBB) and can, therefore, be used as a noninvasive method to target the central nervous system. Furthermore, the addition of the peptide PhP.B to AAV9 increases its transduction across the BBB by 40-fold. Another neurotropic serotype, AAV5, has been shown as a gene therapeutic delivery vehicle to ameliorate several neurodegenerative diseases in preclinical models, but its administration requires invasive surgery. In this study, AAV9-PhP.B and AAV5-PhP.B were designed and produced in an insect cell-based system. To AAV9, the PhP.B peptide TLAVPFK was added, whereas in AAV5-PhP.B (AQTLAVPFKAQAQ), with AQ-AQAQ sequences used to swap with the corresponding sequence of AAV5. The addition of PhP.B to AAV5 did not affect its capacity to cross the mouse BBB, while increased transduction of liver tissue was observed. Then, intravenous (IV) and intrastriatal (IStr) delivery of AAV9-PhP.B and AAV5 were compared. For AAV9-PhP.B, similar transduction and expression levels were achieved in the striatum and cortex, irrespective of the delivery method used. IStr administration of AAV5 resulted in significantly higher amounts of vector DNA and therapeutic miRNA in the target regions such as striatum and cortex when compared with an IV administration of AAV9-PhP.B. These results illustrate the challenge in developing a vector that can be delivered noninvasively while achieving a transduction level similar to that of direct administration of AAV5. Thus, for therapeutic miRNA delivery with high local expression requirements, intraparenchymal delivery of AAV5 is preferred, whereas a humanized AAV9-PhP.B may be useful when widespread brain (and peripheral) transduction is needed.

Authors 7

1. Kimberly L. Pietersz

   Radboud University Nijmegen · UniQure (Netherlands) · Donders Institute for Brain, Cognition and Behaviour · Donders Centre for Neuroscience

   Affiliation as printed

   Department of Molecular Animal Physiology, Faculty of Science, Centre for Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, Netherlands

   Department of Research & Development, uniQure Biopharma B.V., Amsterdam, Netherlands

2. Stephan M. Pouw

   UniQure (Netherlands)

   Affiliation as printed

   Department of Research & Development, uniQure Biopharma B.V., Amsterdam, Netherlands

3. Jolanda M.P. Liefhebber

   UniQure (Netherlands)

   Affiliation as printed

   Department of Research & Development, uniQure Biopharma B.V., Amsterdam, Netherlands

4. Sander J. van Deventer Aachen Department of Gastroenterology and Hepatology

   Leiden University Medical Center · UniQure (Netherlands)

   Affiliation as printed

   Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands

   Department of Research & Development, uniQure Biopharma B.V., Amsterdam, Netherlands

5. Gerard J.M. Martens

   Radboud University Nijmegen · Donders Institute for Brain, Cognition and Behaviour · Donders Centre for Neuroscience

   Affiliation as printed

   Department of Molecular Animal Physiology, Faculty of Science, Centre for Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, Netherlands

6. Pavlina S. Konstantinova

   UniQure (Netherlands)

   Affiliation as printed

   Department of Research & Development, uniQure Biopharma B.V., Amsterdam, Netherlands

7. Bas Blits corresponding

   UniQure (Netherlands)

   Affiliation as printed

   Department of Research & Development, uniQure Biopharma B.V., Amsterdam, Netherlands