Systemic AAVrh10 provides higher transgene expression than AAV9 in the brain and the spinal cord of neonatal mice

Abstract

Systemic delivery of self-complementary (sc) adeno-associated-virus vector of serotype 9 (AAV9) was recently shown to provide robust and widespread gene transfer to the central nervous system (CNS), opening new avenues for practical, and non-invasive gene therapy of neurological diseases. More recently, AAV of serotype rh10 (AAVrh10) was also found highly efficient to mediate CNS transduction after intravenous administration in mice. However, only a few studies compared AAV9 and AAVrh10 efficiencies, particularly in the spinal cord. In this study, we compared the transduction capabilities of AAV9 and AAVrh10 in the brain, the spinal cord, and the peripheral nervous system (PNS) after intravenous delivery in neonatal mice. As reported in previous studies, AAVrh10 achieved either similar or higher transduction than AAV9 in all the examined brain regions. The superiority of AAVrh10 over AAV9 appeared statistically significant only in the medulla and the cerebellum, but a clear trend was also observed in other structures like the hippocampus or the cortex. In contrast to previous studies, we found that AAVrh10 was more efficient than AAV9 for transduction of the dorsal spinal cord and the lower motor neurons (MNs). However, differences between the two serotypes appeared mainly significant at low dose, and surprisingly, increasing the dose did not improve AAVrh10 distribution in the spinal cord, in contrary to AAV9. Similar dose-related differences between transduction efficiency of the two serotypes were also observed in the sciatic nerve. These findings suggest differences in the transduction mechanisms of these two serotypes, which both hold great promise for gene therapy of neurological diseases.

Ultramicroscopy as a novel tool to unravel the tropism of AAV gene therapy vectors in the brain

“…Recent studies applied laborious semi-quantitative methods, i.e., scoring systems to evaluate GFP immunoreactivity in different CNS regions 21 . However, these studies could not detect major differences in hippocampal transduction in the brain and spinal cord of neonatal mice when using AAV9 and AAVrh10 vectors 22 . Using UM, single transduced neurons in hippocampal regions CA1 to 4 were clearly visible which allows for detailed mapping of transduction efficacy.…”

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure

“…Our first goal was to evaluate the transduction efficiency and the specificity of AAV2/9 and 2/rh10 serotypes, which are the main serotypes used to transduce the nervous system, regarding mSC when injected directly in the nerve. In 2015, Tanguy et al [60] observed a cell transduction in the sciatic nerve of mice intravenously injected with AAV2/9 one day after birth but no detail on the cell type was provided. Hoyng et al described in 2015 the transduction efficiency of AAV2/1 to 9 in rat and human Schwann cells in vitro and in sectioned mouse nerve segments undergoing demyelination ex vivo [26].…”

Comparison of Gene Delivery to the Kidney by Adenovirus, Adeno-Associated Virus, and Lentiviral Vectors After Intravenous and Direct Kidney Injections

“…[31][32][33][34][35][36][37][38][39] AAV2 is generally thought to be a weak vector for IV gene therapy, whereas the newer AAVrh10 serotype is thought to be one of the most robust vectors for systemic therapy. [40][41][42][43] While both were near equal in the injected kidney, it was interesting that the more robust AAVrh10 vector produced substantially higher off-target gene delivery in the liver than AAV2. We also observed a dosedependent effect when using AAVrh10-Cre, with markedly more tubule cells being transduced after injecting 1e12 GC versus 2e11 GC ( Supplementary Fig.…”