Abstract

Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5–58) with large deletions in the red/green opsin gene array. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed the existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM.

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cover image Human Gene Therapy
Human Gene Therapy
Volume 24Issue Number 12December 2013
Pages: 993 - 1006
PubMed: 24067079

History

Published in print: December 2013
Published ahead of print: 30 October 2013
Published online: 25 September 2013
Accepted: 22 September 2013
Received: 6 August 2013

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Artur V. Cideciyan
*
Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Robert B. Hufnagel*
Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH 45229.
Division of Pediatric Ophthalmology, Cincinnati Children's Hospital, Cincinnati, OH 45229.
Joseph Carroll
Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI 53226.
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226.
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226.
Alexander Sumaroka
Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Xunda Luo
Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Sharon B. Schwartz
Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Alfredo Dubra
Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI 53226.
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226.
Megan Land
Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI 53226.
Michel Michaelides
UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom EC1V 9EL.
Jessica C. Gardner
UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom EC1V 9EL.
Alison J. Hardcastle
UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom EC1V 9EL.
Anthony T. Moore
UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom EC1V 9EL.
Robert A. Sisk
Division of Pediatric Ophthalmology, Cincinnati Children's Hospital, Cincinnati, OH 45229.
Cincinnati Eye Institute, Cincinnati, OH 45242.
Zubair M. Ahmed
Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH 45229.
Division of Pediatric Ophthalmology, Cincinnati Children's Hospital, Cincinnati, OH 45229.
Susanne Kohl
Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University Tuebingen, 72076 Tuebingen, Germany.
Bernd Wissinger
Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University Tuebingen, 72076 Tuebingen, Germany.
Samuel G. Jacobson
Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Notes

Address correspondence to:Dr. Samuel G. JacobsonScheie Eye InstituteUniversity of Pennsylvania51 N. 39th StreetPhiladelphia, PA 19104E-mail: [email protected]
Dr. Bernd WissingerMolecular Genetics LaboratoryInstitute for Ophthalmic ResearchCentre for OphthalmologyUniversity TuebingenRoentgenweg 1172076 TuebingenGermany
E-mail: [email protected]

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No competing financial interests exist.

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