Key result
Intrastriatal administration of AAV5 achieved a 22-fold and 15-fold higher vector distribution in the striatum and cortex, respectively, compared to intravenous administration of AAV9-PhP.B.
Why the study?
Neurotropic AAV5 requires invasive surgery to target the central nervous system, prompting the design and evaluation of PhP.B-modified AAV vectors for noninvasive delivery across the blood-brain barrier.
Does systemic delivery of AAV9-PhP.B achieve similar brain transduction levels compared to direct intrastriatal administration of AAV5 in a mouse model?
Does systemic delivery of AAV9-PhP.B achieve similar brain transduction levels compared to direct intrastriatal administration of AAV5 in a mouse model?
Effect estimate: 22-fold and 15-fold higher
p-value: p=<0.0001
Direct intraparenchymal delivery of AAV5 provides superior local brain expression compared to systemic delivery of AAV9-PhP.B, though systemic AAV9-PhP.B remains useful for widespread transduction.
Favors direct intraparenchymal AAV for localized brain targets in mice; hypothesis-generating for human neurological gene therapy routes.
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.
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Pietersz et al. (2021) studied Neurodegenerative diseases. AAV5 intrastriatal administration vs. AAV9-PhP.B intravenous administration was evaluated on Vector distribution in the striatum and cortex (22-fold and 15-fold higher, p=<0.0001). Intrastriatal administration of AAV5 achieved a 22-fold and 15-fold higher vector distribution in the striatum and cortex, respectively, compared to intravenous administration of AAV9-PhP.B.
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