Wadih M Zein1, Brett G Jeffrey1, Henry E Wiley1, Amy E Turriff1, Santa J Tumminia1, Weng Tao2, Ronald A Bush3, Dario Marangoni4, Rong Wen5, Lisa L Wei1, Paul A Sieving6. 1. National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States. 2. Neurotech Pharmaceuticals, Inc., Cumberland, Rhode Island, United States. 3. National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States. 4. National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States Department of Biotechnology and Applied Clinical Science, University of L'Aquila, L'Aquila, Italy. 5. Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami, Miller School of Medicine, Miami, Florida, United States. 6. National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States.
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.). Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
RCT Entities:
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 humanretinitis pigmentosa. Recently, CNTF was found to improve cone photoreceptor function in a canineCNGB3achromatopsia model. This study explores whether this finding translates to humans with CNGB3achromatopsia. 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 canineCNGB3 cones in response to CNTF. (ClinicalTrials.gov number, NCT01648452.). Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
Entities:
Keywords:
CNGB3; CNTF; CNTF-releasing implant; ECT implant; achromatopsia; cone photoreceptor; human clinical trial; rod photoreceptor
Authors: S Kohl; B Baumann; M Broghammer; H Jägle; P Sieving; U Kellner; R Spegal; M Anastasi; E Zrenner; L T Sharpe; B Wissinger Journal: Hum Mol Genet Date: 2000-09-01 Impact factor: 6.150
Authors: F Q Liang; T S Aleman; N S Dejneka; L Dudus; K J Fisher; A M Maguire; S G Jacobson; J Bennett Journal: Mol Ther Date: 2001-11 Impact factor: 11.454
Authors: Ronald A Bush; Bo Lei; Weng Tao; Dorit Raz; Chi-Chao Chan; Terry A Cox; Maria Santos-Muffley; Paul A Sieving Journal: Invest Ophthalmol Vis Sci Date: 2004-07 Impact factor: 4.799
Authors: Weng Tao; Rong Wen; Moses B Goddard; Sandy D Sherman; Pam J O'Rourke; Paul F Stabila; William J Bell; Brenda J Dean; Konrad A Kauper; Veronica A Budz; William G Tsiaras; Gregory M Acland; Sue Pearce-Kelling; Alan M Laties; Gustavo D Aguirre Journal: Invest Ophthalmol Vis Sci Date: 2002-10 Impact factor: 4.799
Authors: Venki Sundaram; Caroline Wilde; Jonathan Aboshiha; Jill Cowing; Colin Han; Christopher S Langlo; Ravinder Chana; Alice E Davidson; Panagiotis I Sergouniotis; James W Bainbridge; Robin R Ali; Alfredo Dubra; Gary Rubin; Andrew R Webster; Anthony T Moore; Marko Nardini; Joseph Carroll; Michel Michaelides Journal: Ophthalmology Date: 2013-10-20 Impact factor: 12.079
Authors: Dario Marangoni; Camasamudram Vijayasarathy; Ronald A Bush; Lisa L Wei; Rong Wen; Paul A Sieving Journal: Invest Ophthalmol Vis Sci Date: 2015-10 Impact factor: 4.799
Authors: Jonathan Aboshiha; Adam M Dubis; Joseph Carroll; Alison J Hardcastle; Michel Michaelides Journal: Br J Ophthalmol Date: 2015-03-13 Impact factor: 4.638
Authors: Jonathan Aboshiha; Neruban Kumaran; Angelos Kalitzeos; Chris Hogg; Gary Rubin; Michel Michaelides Journal: Invest Ophthalmol Vis Sci Date: 2017-07-01 Impact factor: 4.799