Multimodal assessment of choroideremia patients defines pre-treatment characteristics
- 449 Downloads
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.
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.
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 mm2 (range 0.30–38.5 mm2), while mean neuroretinal volume (n = 42) was found to be 1.76 ± 0.12 mm3. 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).
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.
KeywordsChoroideremia Gene therapy Autofluorescence Symmetry
The authors wish to acknowledge the help from all colleagues who helped obtain the clinical data on CHM patients in the “RP Sprechstunde” (outpatient clinic for hereditary retinal disorders) over previous decades. Drs. S Biskup, M Preisig, B Weber, and JA van den Hurk contributed to this work by verifying the diagnosis on a genetic level in some of the patients.
Conflict of interest statement
All authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
Gesellschaft zur Förderung der Neuroophthalmologie e.V., Tistou & Charlotte Kerstan Foundation, Pro Retina e.V., UK Medical Research Council (MR/K003690/1);
- 1.Mauthner L (1872) Ein Fall von Chorioideremie. Bericht des Naturwissenschaftlich-Medizinischen Vereins Innsbruck:191–197Google Scholar
- 4.Cremers FP, van de Pol DJ, Wieringa B, Collins FS, Sankila EM, Siu VM, Flintoff WF, Brunsmann F, Blonden LA, Ropers HH (1989) Chromosomal jumping from the DXS165 locus allows molecular characterization of four microdeletions and a de novo chromosome X/13 translocation associated with choroideremia. Proc Natl Acad Sci U S A 86:7510–7514PubMedCentralCrossRefPubMedGoogle Scholar
- 10.Moosajee M, Ramsden SC, Black GC, Seabra MC, Webster AR (2014) Clinical utility gene card for: choroideremia. Eur J Hum Genet 22(4)Google Scholar
- 12.Tolmachova T, Tolmachov OE, Barnard AR, de Silva SR, Lipinski DM, Walker NJ, Maclaren RE, Seabra MC (2013) Functional expression of Rab escort protein 1 following AAV2-mediated gene delivery in the retina of choroideremia mice and human cells ex vivo. J Mol Med 91:825–837PubMedCentralCrossRefPubMedGoogle Scholar
- 13.MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FP, Black GC, Lotery AJ, Downes SM, Webster AR, Seabra MC (2014) Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 383:1129–1137PubMedCentralCrossRefPubMedGoogle Scholar
- 22.Bittner AK (2011) Variability in vision and photopsias in retinitis pigmentosa are related to disease severity and psychosocial factors. Dissertation. The Johns Hopkins UniversityGoogle Scholar