Preclinical testing of AAV9-PHP.B for transgene expression in the non-human primate cochlea.

Hearing Research
Maryna V IvanchenkoCasey A Maguire

Abstract

In a number of mouse models of hereditary deafness, therapeutic transgene delivery to the cochlea and vestibular organs using adeno-associated viral vectors (AAVs) has shown striking rescue of hearing and balance. However, only a subset of AAV capsids have shown efficacy in transducing both inner hair cells and outer hair cells, and it is also not clear which of these can be translated to treatment of human inner ear. We recently reported efficient transgene expression of a GFP reporter in a non-human primate cochlea, in both inner and outer hair cells, following injection of the AAV9 capsid variant PHP.B via the round window membrane (RWM). However efficiency was poor at a lower dose. To further define the transduction potential of AAV9-PHP.B, we have performed a dosing study in the cynomolgus monkey and assessed vector-encoded GFP expression. Three animals were injected in both ears and four doses were tested. We describe a transmastoid surgical approach needed to access the RWM of this common primate model. We found that AAV9-PHP.B transduced nearly 100% of both IHCs and OHCs, from base to apex, at the higher doses (3.5 × 1011 and 7 × 1011 vector genomes). However, at lower doses there was a steep reduction in viral transduc...Continue Reading

Citations

Jul 28, 2020·Journal of Clinical Medicine·Sedigheh Delmaghani, Aziz El-Amraoui
Dec 23, 2020·EMBO Molecular Medicine·Shahar TaiberKaren B Avraham
Jan 11, 2021·EBioMedicine·Christian WrobelTobias Moser
Nov 20, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Jason WuJeffrey R Holt
Apr 6, 2021·Frontiers in Neuroscience·Ryan CraneMuna I Naash
Apr 18, 2021·Trends in Pharmacological Sciences·Cole W PetersKillian S Hanlon
Apr 20, 2021·Molecular Therapy. Methods & Clinical Development·Maryna V IvanchenkoDavid P Corey
May 29, 2021·Scientific Reports·Rachael T RichardsonJames B Fallon
Aug 20, 2021·Life Science Alliance·Cristin D DavidsonWilliam J Pavan
Nov 9, 2021·Frontiers in Cell and Developmental Biology·Maryna V IvanchenkoDavid P Corey

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