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Retinal Structure and Function in Achromatopsia : Implications for Gene Therapy

Sundaram, V.; Wilde, C.; Aboshiha, J.; Cowing, J.; Han, C.; Langlo, C.S.; Chana, R.; Davidson, A.E.; Sergouniotis, P.I.; Bainbridge, J.W.; Ali, R.R.; Dubra, A.; Rubin, G.; Webster, A.R.; Moore, A.T.; Nardini, M.; Carroll, J.; Michaelides, M.

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V. Sundaram

C. Wilde

J. Aboshiha

J. Cowing

C. Han

C.S. Langlo

R. Chana

A.E. Davidson

P.I. Sergouniotis

J.W. Bainbridge

R.R. Ali

A. Dubra

G. Rubin

A.R. Webster

A.T. Moore

J. Carroll

M. Michaelides


Purpose: To characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical trials of gene therapy. Design: Cross-sectional study. Participants: Forty subjects with ACHM. Methods: All subjects underwent spectral domain optical coherence tomography (SD-OCT), microperimetry, and molecular genetic testing. Foveal structure on SD-OCT was graded into 5 distinct categories: (1) continuous inner segment ellipsoid (ISe), (2) ISe disruption, (3) ISe absence, (4) presence of a hyporeflective zone (HRZ), and (5) outer retinal atrophy including retinal pigment epithelial loss. Foveal and outer nuclear layer (ONL) thickness was measured and presence of hypoplasia determined. Main Outcome Measures: Photoreceptor appearance on SD-OCT imaging, foveal and ONL thickness, presence of foveal hypoplasia, retinal sensitivity and fixation stability, and association of these parameters with age and genotype. Results: Forty subjects with a mean age of 24.9 years (range, 6e52 years) were included. Disease-causing variants were found in CNGA3 (n [ 18), CNGB3 (n ¼ 15), GNAT2 (n ¼ 4), and PDE6C (n ¼ 1). No variants were found in 2 individuals. In all, 22.5% of subjects had a continuous ISe layer at the fovea, 27.5% had ISe disruption, 20% had an absent ISe layer, 22.5% had an HRZ, and 7.5% had outer retinal atrophy. No significant differences in age (P ¼ 0.77), mean retinal sensitivity (P ¼ 0.21), or fixation stability (P ¼ 0.34) across the 5 SD-OCT categories were evident. No correlation was found between age and foveal thickness (P ¼ 0.84) or between age and foveal ONL thickness (P ¼ 0.12). Conclusions: The lack of a clear association of disruption of retinal structure or function in ACHM with age suggests that the window of opportunity for intervention by gene therapy is wider in some individuals than previously indicated. Therefore, the potential benefit for a given subject is likely to be better predicted by specific measurement of photoreceptor structure rather than simply by age. The ability to directly assess cone photoreceptor preservation with SD-OCT and/or adaptive optics imaging is likely to prove invaluable in selecting subjects for future trials and measuring the trials’ impact.


Sundaram, V., Wilde, C., Aboshiha, J., Cowing, J., Han, C., Langlo, C., …Michaelides, M. (2014). Retinal Structure and Function in Achromatopsia : Implications for Gene Therapy. Ophthalmology, 121(1), 234-245.

Journal Article Type Article
Acceptance Date Aug 13, 2013
Online Publication Date Oct 19, 2013
Publication Date Jan 1, 2014
Deposit Date Nov 4, 2013
Publicly Available Date Mar 2, 2016
Journal Ophthalmology: Journal of The American Academy of Ophthalmology
Print ISSN 0161-6420
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 121
Issue 1
Pages 234-245


Accepted Journal Article (2.2 Mb)

Copyright Statement
NOTICE: this is the author’s version of a work that was accepted for publication in Ophthalmology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Ophthalmology, 121, 1, January 2014, 10.1016/j.ophtha.2013.08.017.

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