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Gene Therapy Reforms Photoreceptor Structure and Restores Vision in NPHP5-associated Leber Congenital Amaurosis

Gustavo D. Aguirre, Artur V. Cideciyan, Valérie L. Dufour, Ana Ripolles García, Raghavi Sudharsan, Malgorzata Swider, Roman Nikonov, Simone Iwabe, Sanford L. Boye, William W. Hauswirth, Samuel G. Jacobson, William A. Beltran
doi: https://doi.org/10.1101/2020.10.07.329821
Gustavo D. Aguirre
aDivision of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
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  • For correspondence: gda@vet.upenn.edu wbeltran@vet.upenn.edu
Artur V. Cideciyan
bScheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Valérie L. Dufour
aDivision of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Ana Ripolles García
aDivision of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Raghavi Sudharsan
aDivision of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Malgorzata Swider
bScheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Roman Nikonov
aDivision of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Simone Iwabe
aDivision of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Sanford L. Boye
cPowell Gene Therapy Center, Department of Pediatrics, University of Florida, Gainesville, FL 32610
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William W. Hauswirth
dDepartment of Ophthalmology, University of Florida, Gainesville, FL 32610
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Samuel G. Jacobson
bScheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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William A. Beltran
aDivision of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
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  • For correspondence: gda@vet.upenn.edu wbeltran@vet.upenn.edu
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Abstract

The inherited childhood blindness caused by mutations in NPHP5, a form of Leber congenital amaurosis, results in abnormal development, dysfunction and degeneration of photoreceptors. A naturally occurring NPHP5 mutation in dogs results in a phenotype that very nearly duplicates the human retinopathy in terms of the photoreceptors involved, spatial distribution of degeneration and the natural history of vision loss. We show that AAV-mediated NPHP5 gene augmentation of mutant canine retinas at the time of active degeneration and peak cell death stably restores photoreceptor structure, function, and vision with either the canine or human NPHP5 transgenes. Mutant cone photoreceptors, which failed to form outer segments during development, reform this structure after treatment. Degenerating rod photoreceptor outer segments are stabilized and develop normal structure. This process begins within 8 weeks following treatment, and remains stable throughout the 6 month post treatment period. In both photoreceptor cell classes, mislocalization of rod and cone opsins is minimized or reversed. Retinal function and functional vision are restored. Efficacy of gene therapy in this large animal ciliopathy model of Leber congenital amaurosis provides a path for translation to human treatment.

Competing Interest Statement

Gustavo D. Aguirre, William A. Beltran, Sanford L. Boye, Artur V. Cideciyan, William W. Hauswirth and Samuel G. Jacobson have filed a methods patent application for NPHP5 gene therapy on behalf of The University of Pennsylvania and the University of Florida. In addition, Sanford L. Boye owns stock in, and is a paid consultant for the company Atsena Therapeutics and William W. Hauswirth owns stock in the companies AGTC and BionicSight, is a paid consultant and a member of the scientific board of AGTC.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 08, 2020.
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Gene Therapy Reforms Photoreceptor Structure and Restores Vision in NPHP5-associated Leber Congenital Amaurosis
Gustavo D. Aguirre, Artur V. Cideciyan, Valérie L. Dufour, Ana Ripolles García, Raghavi Sudharsan, Malgorzata Swider, Roman Nikonov, Simone Iwabe, Sanford L. Boye, William W. Hauswirth, Samuel G. Jacobson, William A. Beltran
bioRxiv 2020.10.07.329821; doi: https://doi.org/10.1101/2020.10.07.329821
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Gene Therapy Reforms Photoreceptor Structure and Restores Vision in NPHP5-associated Leber Congenital Amaurosis
Gustavo D. Aguirre, Artur V. Cideciyan, Valérie L. Dufour, Ana Ripolles García, Raghavi Sudharsan, Malgorzata Swider, Roman Nikonov, Simone Iwabe, Sanford L. Boye, William W. Hauswirth, Samuel G. Jacobson, William A. Beltran
bioRxiv 2020.10.07.329821; doi: https://doi.org/10.1101/2020.10.07.329821

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