Immanuel P Seitz1,2, Ahmad Zhour1, Susanne Kohl2, Pablo Llavona2, Tobias Peter3, Barbara Wilhelm3, Eberhart Zrenner1,2, Marius Ueffing2, Karl Ulrich Bartz-Schmidt1, M Dominik Fischer4,5,6,7. 1. University Eye Hospital, University of Tübingen, Tübingen, Germany. 2. Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany. 3. STZ Eyetrial, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany. 4. University Eye Hospital, University of Tübingen, Tübingen, Germany. dominik.fischer@ndcn.ox.ac.uk. 5. Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, UK. dominik.fischer@ndcn.ox.ac.uk. 6. Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, UK. dominik.fischer@ndcn.ox.ac.uk. 7. Merton College, University of Oxford, Oxford, OX1 4JD, UK. dominik.fischer@ndcn.ox.ac.uk.
Abstract
PURPOSE: 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). CONCLUSION: 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.
PURPOSE: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 CHMpatients 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). CONCLUSION: 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 CHMpatients provides important evidence of the natural rate of disease progression and degree of symmetry between eyes.
Authors: Mariya Moosajee; Simon C Ramsden; Graeme C M Black; Miguel C Seabra; Andrew R Webster Journal: Eur J Hum Genet Date: 2013-08-21 Impact factor: 4.246
Authors: M Dominik Fischer; Johannes C Fleischhauer; Mark C Gillies; Florian K Sutter; Horst Helbig; Daniel Barthelmes Journal: Invest Ophthalmol Vis Sci Date: 2008-04-25 Impact factor: 4.799
Authors: F P Cremers; D J van de Pol; P J Diergaarde; B Wieringa; R L Nussbaum; M Schwartz; H H Ropers Journal: Genomics Date: 1989-01 Impact factor: 5.736
Authors: F P Cremers; D J van de Pol; B Wieringa; F S Collins; E M Sankila; V M Siu; W F Flintoff; F Brunsmann; L A Blonden; H H Ropers Journal: Proc Natl Acad Sci U S A Date: 1989-10 Impact factor: 11.205
Authors: M Dominik Fischer; Gabriel Willmann; Andreas Schatz; Kai Schommer; Ahmad Zhour; Eberhart Zrenner; Karl U Bartz-Schmidt; Florian Gekeler Journal: PLoS One Date: 2012-04-30 Impact factor: 3.240
Authors: Tanya Tolmachova; Oleg E Tolmachov; Alun R Barnard; Samantha R de Silva; Daniel M Lipinski; Nathan J Walker; Robert E Maclaren; Miguel C Seabra Journal: J Mol Med (Berl) Date: 2013-06-12 Impact factor: 4.599
Authors: Robert E MacLaren; Markus Groppe; Alun R Barnard; Charles L Cottriall; Tanya Tolmachova; Len Seymour; K Reed Clark; Matthew J During; Frans P M Cremers; Graeme C M Black; Andrew J Lotery; Susan M Downes; Andrew R Webster; Miguel C Seabra Journal: Lancet Date: 2014-01-16 Impact factor: 79.321
Authors: Immanuel P Seitz; Jasleen K Jolly; M Dominik Fischer; Matthew P Simunovic Journal: Graefes Arch Clin Exp Ophthalmol Date: 2018-02-05 Impact factor: 3.117
Authors: Liangbo L Shen; Aneesha Ahluwalia; Mengyuan Sun; Benjamin K Young; Holly K Grossetta Nardini; Lucian V Del Priore Journal: Ophthalmol Retina Date: 2020-03-14
Authors: Tomas S Aleman; Grace Han; Leona W Serrano; Nicole M Fuerst; Emily S Charlson; Denise J Pearson; Daniel C Chung; Anastasia Traband; Wei Pan; Gui-Shuang Ying; Jean Bennett; Albert M Maguire; Jessica I W Morgan Journal: Ophthalmology Date: 2016-12-13 Impact factor: 12.079
Authors: Liangbo L Shen; Aneesha Ahluwalia; Mengyuan Sun; Benjamin K Young; Holly K Grossetta Nardini; Lucian V Del Priore Journal: Br J Ophthalmol Date: 2020-05-29 Impact factor: 5.908
Authors: Jasleen K Jolly; Thomas L Edwards; Jonathan Moules; Markus Groppe; Susan M Downes; Robert E MacLaren Journal: Invest Ophthalmol Vis Sci Date: 2016-08-01 Impact factor: 4.799
Authors: Jasleen K Jolly; Kanmin Xue; Thomas L Edwards; Markus Groppe; Robert E MacLaren Journal: Invest Ophthalmol Vis Sci Date: 2017-10-01 Impact factor: 4.799