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Mays Talib, Mary van Schooneveld, Jan Wijnholds, Maria M van Genderen, N. Schalij-Delofs, Ralph Florijn, Frans P Cremers, Ingeborgh Born, Alberta A H J Thiadens, Carel C B Hoyng, Caroline C W Klaver, Arthur A Bergen, Camiel Boon; Extensive phenotyping in CRB1-associated retinal dystrophies: defining clinical endpoints for gene therapy trials. Invest. Ophthalmol. Vis. Sci. 2018;59(9):43. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
CRB1 mutations are associated with severe retinal dystrophies (RD). As human CRB1 gene therapy is under development, defining optimal endpoints for a CRB1 gene therapy trial is essential. We performed a cross-sectional clinical study to investigate the retinal structure and function in patients with CRB1-RD.
Patients with genetically confirmed CRB1-RD (n=19; aged 6-53; mean 24.1 years), of whom 9 were from a genetic isolate (GI), and who had a best-corrected visual acuity (BCVA) ≥0.05 at the last visit, were studied with ETDRS BCVA, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, Goldmann visual field (VF), microperimetry, full-field electroretinography (ERG), and full-field stimulus testing (FST).
Patients had retinitis pigmentosa (RP; n=17; GI and non-GI), cone-rod dystrophy (CORD; n=1; GI), or macular dystrophy (n=1; non-GI). Median age at first symptom onset was 2 years (range 0.8-17) in RP patients, and 11-34 years in the other 2 patients. Median decimal BCVA in the better and worse seeing eye was 0.22 (range 0.05-0.83) and 0.07 (range light perception-0.72), respectively. Patients with severe visual impairment were younger (n=4; median age 9.5) than those with low (n=9; median age 26) or (sub)normal vision (n=6; median age 26.5; p=0.03). VF diameter was <70° in ≥1 eye in 17 RP patients, but relatively preserved in the CORD and macular dystrophy patients. Mean macular threshold sensitivity was 8.5 dB (±6.9; range 0.4-25.3). Fixation stability declined in eyes with a mean threshold sensitivity <7 dB (n=13). SD-OCT showed cystoid maculopathy in 8 subjects aged 10-39; inner retinal thickening (15 patients); and relative preservation of foveal ellipsoid zone and external limiting membrane in 13 and 10 subjects (RP and CORD), respectively, aged 9-53. All retinal layers were discernible in 14 patients, while in the others, lamination was coarse. FST provided an outcome measure in eyes with (nearly) extinguished ERG amplitudes.
CRB1-RDs have a severe clinical course, but symptom onset may vary and some patients retain central visual function at advanced ages. Diagnoses may vary within the same family. BCVA is variable across ages, but imaging and functional studies indicate that the (gene) therapeutic window of opportunity spans the first 3 decades of life in most patients.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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