Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate

Eva Andres-Mateos,Luk H Vandenberghe,Fotini Nicolaou,Konstantina M Stankovic,Brian M Lin,Jean Phillips,William F Sewell,Carmen Unzu,Julio Sanmiguel,Kathrin I Bourdeu,Michael J Mckenna,Michelle D Valero,Rudolph J Beiler,Nicholas A Dewyer,Lukas D Landegger

doi:10.1038/s41467-022-28969-3

Abstract

Inner ear gene therapy using adeno-associated viral vectors (AAV) promises to alleviate hearing and balance disorders. We previously established the benefits of Anc80L65 in targeting inner and outer hair cells in newborn mice. To accelerate translation to humans, we now report the feasibility and efficiency of the surgical approach and vector delivery in a nonhuman primate model. Five rhesus macaques were injected with AAV1 or Anc80L65 expressing eGFP using a transmastoid posterior tympanotomy approach to access the round window membrane after making a small fenestra in the oval window. The procedure was well tolerated. All but one animal showed cochlear eGFP expression 7–14 days following injection. Anc80L65 in 2 animals transduced up to 90% of apical inner hair cells; AAV1 was markedly less efficient at equal dose. Transduction for both vectors declined from apex to base. These data motivate future translational studies to evaluate gene therapy for human hearing disorders.

Highlights

Inner ear gene therapy using adeno-associated viral vectors (AAV) promises to alleviate hearing and balance disorders
Due to the novelty of the construct and the promoter combination in the cochlea, prior to injection in nonhuman primate (NHP), AAV2/1.CB7.chimeric intron (CI).enhanced green fluorescent protein (eGFP).RBG and AAV2/Anc80L65.CB7.CI.eGFP.RBG were tested in wild-type mice by systemic and cochlear injection
In line with expectations for AAV1 and Anc80L65, differential levels of enhanced green fluorescent protein expression were detected in the murine livers with both vectors after intravenous delivery (Supplementary Fig. 1a)[28]

Summary

Introduction

Inner ear gene therapy using adeno-associated viral vectors (AAV) promises to alleviate hearing and balance disorders. Anc80L65 in 2 animals transduced up to 90% of apical inner hair cells; AAV1 was markedly less efficient at equal dose. Transduction for both vectors declined from apex to base. Based on data from a panoply of available AAV capsids, the proteinaceous shell that protects a single-stranded DNA genome is a major determinant of its targeting, immunological, and other properties These attributes continue to justify the increasing utility of AAV in clinical gene therapy applications across various fields and the approval of two AAV-based drug products[20]

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