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; Luk H Vandenberghe

doi:10.1038/s41467-022-28969-3

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

Nat Commun. 2022 Mar 15;13(1):1359. doi: 10.1038/s41467-022-28969-3.

Authors

Eva Andres-Mateos^#^{1

2

3}, Lukas D Landegger^#^{4

5

6}, Carmen Unzu^#^{1

2}, Jean Phillips⁵, Brian M Lin⁵, Nicholas A Dewyer⁵, Julio Sanmiguel^{1

2}, Fotini Nicolaou^{1

2}, Michelle D Valero^{4

5}, Kathrin I Bourdeu⁷, William F Sewell^{4

5}, Rudolph J Beiler⁸, Michael J McKenna^{9

10

11

12

13}, Konstantina M Stankovic^{14

15

16

17

18}, Luk H Vandenberghe^{19

20

21

22}

Affiliations

¹ Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear, Boston, MA, 02114, USA.
² Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA.
³ Akouos Inc., 645 Summer St, Suite 200, Boston, MA, 02210, USA.
⁴ Eaton Peabody Laboratories, Massachusetts Eye and Ear, Boston, MA, 02114, USA.
⁵ Department of Otolaryngology - Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA, 02114, USA.
⁶ Department of Otolaryngology, Vienna General Hospital and Medical University of Vienna, Vienna, 1090, Austria.
⁷ Department of Anesthesiology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA.
⁸ Animal Science Center, Boston University, Boston, MA, 02118, USA.
⁹ Eaton Peabody Laboratories, Massachusetts Eye and Ear, Boston, MA, 02114, USA. mmckenna@akouos.com.
¹⁰ Department of Otolaryngology - Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA, 02114, USA. mmckenna@akouos.com.
¹¹ Otopathology Laboratory, Massachusetts Eye and Ear, Boston, MA, 02114, USA. mmckenna@akouos.com.
¹² Speech and Hearing Bioscience and Technology Program, Harvard University, Cambridge, MA, 02138, USA. mmckenna@akouos.com.
¹³ Akouos Inc., 645 Summer St, Suite 200, Boston, MA, 02210, USA. mmckenna@akouos.com.
¹⁴ Eaton Peabody Laboratories, Massachusetts Eye and Ear, Boston, MA, 02114, USA. kstankovic@stanford.edu.
¹⁵ Department of Otolaryngology - Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA, 02114, USA. kstankovic@stanford.edu.
¹⁶ Speech and Hearing Bioscience and Technology Program, Harvard University, Cambridge, MA, 02138, USA. kstankovic@stanford.edu.
¹⁷ Harvard Stem Cell Institute, Harvard University, Cambridge, 02138, MA, USA. kstankovic@stanford.edu.
¹⁸ Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA. kstankovic@stanford.edu.
¹⁹ Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear, Boston, MA, 02114, USA. luk_vandenberghe@meei.harvard.edu.
²⁰ Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA. luk_vandenberghe@meei.harvard.edu.
²¹ Harvard Stem Cell Institute, Harvard University, Cambridge, 02138, MA, USA. luk_vandenberghe@meei.harvard.edu.
²² The Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. luk_vandenberghe@meei.harvard.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cochlea / physiology
Dependovirus* / genetics
Gene Transfer Techniques
Genetic Therapy / methods
Genetic Vectors* / genetics
Macaca mulatta / genetics
Mice

Grants and funding

R01 DC015824/DC/NIDCD NIH HHS/United States