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

Eva Andres-Mateos, Lukas D. Landegger, Carmen Unzu, Jean Phillips, Brian M. Lin, Nicholas A. Dewyer, Julio Sanmiguel, Fotini Nicolaou, Michelle D. Valero, Kathrin I. Bourdeu, William F. Sewell, Rudolph J. Beiler, Michael J. McKenna (), Konstantina M. Stankovic () and Luk H. Vandenberghe ()
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Eva Andres-Mateos: Schepens Eye Research Institute and Massachusetts Eye and Ear
Lukas D. Landegger: Eaton Peabody Laboratories, Massachusetts Eye and Ear
Carmen Unzu: Schepens Eye Research Institute and Massachusetts Eye and Ear
Jean Phillips: Massachusetts Eye and Ear and Harvard Medical School
Brian M. Lin: Massachusetts Eye and Ear and Harvard Medical School
Nicholas A. Dewyer: Massachusetts Eye and Ear and Harvard Medical School
Julio Sanmiguel: Schepens Eye Research Institute and Massachusetts Eye and Ear
Fotini Nicolaou: Schepens Eye Research Institute and Massachusetts Eye and Ear
Michelle D. Valero: Eaton Peabody Laboratories, Massachusetts Eye and Ear
Kathrin I. Bourdeu: Massachusetts Eye and Ear, Harvard Medical School
William F. Sewell: Eaton Peabody Laboratories, Massachusetts Eye and Ear
Rudolph J. Beiler: Boston University
Michael J. McKenna: Eaton Peabody Laboratories, Massachusetts Eye and Ear
Konstantina M. Stankovic: Eaton Peabody Laboratories, Massachusetts Eye and Ear
Luk H. Vandenberghe: Schepens Eye Research Institute and Massachusetts Eye and Ear

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28969-3

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