title: CNGB3-achromatopsia clinical trial with CNTF: diminished rod pathway responses with no evidence of improvement in cone function.
abstract: OBJECTIVE
  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.).
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Wadih M
authors.initials: WM
authors.lastname: Zein
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Brett G
authors.initials: BG
authors.lastname: Jeffrey
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Henry E
authors.initials: HE
authors.lastname: Wiley
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Turriff
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Santa J
authors.initials: SJ
authors.lastname: Tumminia
authors.affiliation: Neurotech Pharmaceuticals, Inc., Cumberland, Rhode Island, United States.
authors.forename: Weng
authors.initials: W
authors.lastname: Tao
authors.affiliation: National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Bush
authors.affiliation: 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.
authors.forename: Dario
authors.initials: D
authors.lastname: Marangoni
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami, Miller School of Medicine, Miami, Florida, United States.
authors.forename: Rong
authors.initials: R
authors.lastname: Wen
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sieving
mesh_terms: D000328:Adult; D002214:Capsules; D020934:Ciliary Neurotrophic Factor / Q000008:administration & dosage*; D003117:Color Vision Defects / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism*; D003623:Dark Adaptation; D004343:Drug Implants; D004596:Electroretinography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D041623:Tomography, Optical Coherence; D055815:Young Adult
chemical_list: C415904:CNGB3 protein, human; D002214:Capsules; D020934:Ciliary Neurotrophic Factor; D054815:Cyclic Nucleotide-Gated Cation Channels; D004343:Drug Implants
keywords: CNGB3; CNTF; CNTF-releasing implant; ECT implant; achromatopsia; cone photoreceptor; human clinical trial; rod photoreceptor