Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the CEP290 Gene

Abstract

Efficacy would be a quantitative change in foveal cone function and possibly distal laminar structure. FST provides a subjective photoreceptor-based outcome; OCT and NIR-RAFI can assess photoreceptor and RPE structure. TPLR and OCI can provide objective measures of postretinal transmission. Minimal change over a decade indicates that there is no practical value in natural history studies.

Pupillary Light Reflexes in Severe Photoreceptor Blindness Isolate the Melanopic Component of Intrinsically Photosensitive Retinal Ganglion Cells

“…Not unexpectedly, these patients tend to have a transient PLR that is similar to a normal response in terms of latency, velocity, and amplitude, especially when adjusted for loss of light sensitivity of the underlying outer retinal photoreceptors. 8,23,27,28,31–36 Patients included in the current work (Supplementary Table S1) represent the most severe end of the LCA spectrum with barely detectable or undetectable light pereceptions, and they tend to show no detectable PLR to the standard short and bright stimulus in the dark. 27,28,31–33 Pupil diameter recordings from representatives of such LCA patients include P13 (a 24-year-old with NLP due to CEP290 mutations; Fig.…”

“…In general, the variability of the slow PLR in severe LCA was not greater than the fast PLR in less severe forms of LCA. 32 …”

“…46−48 Some genetic forms of LCA, such as those caused by GUCY2D , demonstrate near normal photoreceptor structure. 30,31,49 Other forms, such as those caused by CEP290 or NPHP5 , show retained central cone photoreceptor, 24,26,29,30,32,50,51 and yet others, such as RPGRIP1 and AIPL1 , are associated with widespread outer retinal degeneration. 25,27,30 Inner retinal structures, such as retinal ganglion cells and the nerve fiber layer, are often retained on OCT 49,52 and on histology.…”

“…Retinal structure and function phenotype from most of the patients have been published previously. 24–32 Excluded were data from six patients (three with CEP290 and one each with NPHP5 , RPGRIP1 , and GUCY2D mutations) with LP vision but detectable transient PLRs to our standard short stimulus, as well as two patients (one AIPL1 and one GUCY2D ) in whom visibility of pupils during the stimulus was obstructed. All subjects were treated in accordance with the tenets of the Declaration of Helsinki, and informed consents were obtained from all patients.…”

“…Pupillometer I was the “standard” equipment reported previously. 27,28,31–37 In brief, white full-field stimuli of short (0.1 second) or long (5 seconds) duration were used with a maximum luminance of 2.5 log scot-cd.m −2 (2.4 log phot-cd.m −2 ) presented monocularly in the dark-adapted (>1 hour) state. For each stimulus presented, video clips were digitized (PMR-202, iRecord Pro+; Streaming Networks, Inc., Santa Clara, CA, USA) from ∼5 seconds before stimulus onset up to ∼30 seconds after stimulus offset.…”