Multimodal assessment of choroideremia patients defines pre-treatment characteristics.
OBJECTIVE
Choroideremia (CHM) is a X-chromosomal disorder leading to blindness by progressive degeneration of choroid, retinal pigment epithelium (RPE), and retinal neurons. A current clinical gene therapy trial (NCT01461213) showed promising safety and efficacy data in a carefully selected patient population. The present study was performed to shed light on pre-treatment characteristics of a larger cohort of CHM patients using a high resolution multi-modal approach.


METHODS
In a retrospective cross-sectional study, data from 58 eyes of 29 patients with clinically confirmed CHM were analysed including best-corrected visual acuity (BCVA), refractive error, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), perimetry, and tonometry. Residual retinal volume, area of residual RPE, and foveal thickness were quantified to further define natural disease progression and assess symmetry.


RESULTS
We evaluated 98 data points of BCVA [0.34 ± 0.06 (logMAR); mean ± 95 % confidence interval], 80 of IOP (14.6 ± 0.6 mmHg), and 98 of refraction (-2.16 ± 1.08 spherical equivalent). Visual fields (n  = 76) demonstrated variable degrees of concentric constriction (54 % <10°, 25 % 10-30°, 21 % >30°). Mean residual RPE area on FAF (n  = 64) measured 8.47 ± 1.91 mm(2) (range 0.30-38.5 mm(2)), while mean neuroretinal volume (n  = 42) was found to be 1.76 ± 0.12 mm(3). Age at examination was exponentially associated with BCVA, while logarithmic functions best described progressive loss of retinal area and volume. A high degree of left to right symmetry was found in all modalities with structural markers showing the best correlation (r (2) area = 0.83; r (2) volume = 0.75).


CONCLUSIONS
Analysis of these widely available clinical data defines the natural disease characteristics of a relevant patient population eligible for gene therapeutic intervention. In the wake of preliminary reports on safety and efficacy of CHM gene therapy (NCT01461213), this multi-modal assessment of a cohort of CHM patients provides important evidence of the natural rate of disease progression and degree of symmetry between eyes.
University Eye Hospital, University of Tübingen, Tübingen, Germany.|Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
Immanuel P
IP
Seitz
University Eye Hospital, University of Tübingen, Tübingen, Germany.
Ahmad
A
Zhour
Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
Susanne
S
Kohl
Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
Pablo
P
Llavona
STZ Eyetrial, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
Tobias
T
Peter
STZ Eyetrial, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
Barbara
B
Wilhelm
University Eye Hospital, University of Tübingen, Tübingen, Germany.|Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
Eberhart
E
Zrenner
Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
Marius
M
Ueffing
University Eye Hospital, University of Tübingen, Tübingen, Germany.
Karl Ulrich
KU
Bartz-Schmidt
University Eye Hospital, University of Tübingen, Tübingen, Germany. dominik.fischer@ndcn.ox.ac.uk.|Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, UK. dominik.fischer@ndcn.ox.ac.uk.|Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, UK. dominik.fischer@ndcn.ox.ac.uk.|Merton College, University of Oxford, Oxford, OX1 4JD, UK. dominik.fischer@ndcn.ox.ac.uk.
M Dominik
MD
Fischer
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015794:Choroideremia / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D003430:Cross-Sectional Studies; D005260:Female; D005451:Fluorescein Angiography; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D009154:Mutation; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D014792:Visual Acuity / Q000502:physiology; D058609:Visual Field Tests; D014794:Visual Fields / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human
Autofluorescence; Choroideremia; Gene therapy; Symmetry