CNGB3-achromatopsia clinical trial with CNTF: diminished rod pathway responses with no evidence of improvement in cone function

Abstract

Purpose: Ciliary neurotrophic factor (CNTF) protects rod photoreceptors from retinal degenerative disease in multiple nonhuman models. Thus far, CNTF has failed to demonstrate rod protection in trials for human retinitis pigmentosa. Recently, CNTF was found to improve cone photoreceptor function in a canine CNGB3 achromatopsia model. This study explores whether this finding translates to humans with CNGB3 achromatopsia.

Methods: A five-subject, open-label Phase I/II study was initiated by implanting intraocular microcapsules releasing CNTF (nominally 20 ng/d) into one eye each of CNGB3 achromat participants. Fellow eyes served as untreated controls. Subjects were followed for 1 year.

Results: Pupil constriction in treated eyes gave evidence of intraocular CNTF release. Additionally, scotopic ERG responses were reduced, and dark-adapted psychophysical absolute thresholds were increased, attributable to diminished rod or rod pathway activity. Optical coherence tomography revealed that the cone-rich fovea underwent structural changes as the foveal hyporeflective zone (HRZ) became diminished in CNTF-treated eyes. No objectively measurable enhancement of cone function was found by assessments of visual acuity, mesopic increment sensitivity threshold, or the photopic ERG. Careful measurements of color hue discrimination showed no change. Nonetheless, subjects reported beneficial changes of visual function in the treated eyes, including reduced light sensitivity and aversion to bright light, which may trace to decreased effective ambient light from the pupillary constriction; further they noted slowed adaptation to darkness, consistent with CNTF action on rod photoreceptors.

Conclusions: Ciliary neurotrophic factor did not measurably enhance cone function, which reveals a species difference between human and canine CNGB3 cones in response to CNTF. (ClinicalTrials.gov number, NCT01648452.).

Keywords: CNGB3; CNTF; CNTF-releasing implant; ECT implant; achromatopsia; cone photoreceptor; human clinical trial; rod photoreceptor.

Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Figures

Figure 1

Color discrimination of participant 003 at 12 months. (A) Anomaloscope matches from the treated (open purple triangles) and untreated eyes (black circles) along with linear regressions over the matching range. Red and green dashed lines show expected matches for protans and deutans, respectively. (B) Low-vision version of the Cambridge Color Test: color discrimination thresholds from the treated (open purple triangles) and untreated eyes (black circles). All thresholds are at or adjacent to the maximum gamut (triangle) that could be produced by the monitor. Curved line shows CIE 1976 L*u*v* space. Red, green, and blue lines indicate protan, deutan, and tritan confusion lines, respectively.

Figure 2

Retinal function of participant 002 following CNTF. (A) Rod- and cone-mediated ERGs from participant 002. Dark-adapted dim flash rod responses (0.01 ERG, upper panel), from the CNTF-treated eye (green) are consistently smaller at 1, 3, 6, and 12 months post implantation compared with the untreated eye (red). The decrease in the CNTF treated eye is less pronounced for the dark-adapted bright flash response (30.0 ERG, middle panel). No cone-mediated responses were obtained to the light-adapted standard flash 3.0 ERG, (lower panel) at any visit. Two baseline evaluations were performed. (B) Mean ERG amplitude ratios (treated/nontreated) at 1 to 12 months post surgery normalized to presurgery baseline (0 months) for the ISCEV dark-adapted dim flash (DA 0.01) and maximal (DA 3.0) responses. Asterisk indicates that the reduction in the ratio for the dim flash amplitude was borderline significant (p[Bonferroni] < 0.075) at 6 months post surgery. (C) Logarithmic difference in absolute psychophysical dark-adapted thresholds were elevated between 1 to 12 months post surgery; asterisk indicates borderline significance at 6 months (p[Bonferroni] < 0.055).

Figure 3

Serial foveal SD-OCT scans from participant 001 over the duration of the trial (A–E). As previously described for achromats (24–28), all eyes at baseline and untreated have a foveal HRZ deep in the retina; this is limited exclusively to the center of the fovea, extends approximately 400 μm and lies just above the bright RPE line. In untreated eyes, this HRZ has an abrupt squared-off edge at each end. The HRZ architecture changes and is no longer apparent in CNTF treated eyes. Treated eye at baseline (A), 1 month (B), 3 months (C), 6 months (D), and 12 months (E), respectively. (F–I) Untreated eye at baseline, months 1, 3, and 6, respectively. (J) Control scan from a normal eye.