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Multimodal assessment of choroideremia patients defines pre-treatment characteristics

  • Immanuel P. Seitz
  • Ahmad Zhour
  • Susanne Kohl
  • Pablo Llavona
  • Tobias Peter
  • Barbara Wilhelm
  • Eberhart Zrenner
  • Marius Ueffing
  • Karl Ulrich Bartz-Schmidt
  • M. Dominik Fischer
Retinal Disorders

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 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).

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.

Keywords

Choroideremia Gene therapy Autofluorescence Symmetry 

Notes

Acknowledgments

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.

Grant support

Gesellschaft zur Förderung der Neuroophthalmologie e.V., Tistou & Charlotte Kerstan Foundation, Pro Retina e.V., UK Medical Research Council (MR/K003690/1);

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Immanuel P. Seitz
    • 1
    • 2
  • Ahmad Zhour
    • 1
  • Susanne Kohl
    • 2
  • Pablo Llavona
    • 2
  • Tobias Peter
    • 3
  • Barbara Wilhelm
    • 3
  • Eberhart Zrenner
    • 1
    • 2
  • Marius Ueffing
    • 2
  • Karl Ulrich Bartz-Schmidt
    • 1
  • M. Dominik Fischer
    • 1
    • 4
    • 5
    • 6
  1. 1.University Eye HospitalUniversity of TübingenTübingenGermany
  2. 2.Institute for Ophthalmic ResearchUniversity of TübingenTübingenGermany
  3. 3.STZ Eyetrial, Centre for OphthalmologyUniversity of TübingenTübingenGermany
  4. 4.Nuffield Laboratory of OphthalmologyUniversity of OxfordOxfordUK
  5. 5.Oxford Eye HospitalOxford University Hospitals NHS TrustOxfordUK
  6. 6.Merton CollegeUniversity of OxfordOxfordUK

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