title: Outcome measure for the treatment of cone photoreceptor diseases: orientation to a scene with cone-only contrast.
abstract: BACKGROUND
  Inherited retinal degenerations (IRDs) preferentially affecting cone photoreceptor function are being considered for treatment trials aiming to improve day vision. The purpose of the current work was to develop cone-specific visual orientation outcomes that can differentiate day vision improvement in the presence of retained night vision.
  
  
  METHODS
  A lighted wall (1.4 m wide, 2 m high) resembling a beaded curtain was formed with 900 individually addressable red, blue and green LED triplets placed in 15 vertical strips hanging 0.1 m apart. Under computer control, different combination of colors and intensities were used to produce the appearance of a door on the wall. Scotopically-matched trials were designed to be perceptible to the cone-, but not rod-, photoreceptor based visual systems. Unmatched control trials were interleaved at each luminance level to determine the existence of any vision available for orientation. Testing started with dark-adapted eyes and a scene luminance attenuated 8 log units from the maximum attainable, and continued with progressively increasing levels of luminance. Testing was performed with a three-alternative forced choice method in healthy subjects and patients with Leber congenital amaurosis (LCA) caused by mutations in GUCY2D, the gene that encodes retinal guanylate cyclase-1.
  
  
  RESULTS
  Normal subjects could perform the orientation task using cone vision at 5 log attenuation and brighter luminance levels. Most GUCY2D-LCA patients failed to perform the orientation task with scotopically-matched test trials at any luminance level even though they were able to perform correctly with unmatched control trials. These results were consistent with a lack of cone system vision and use of the rod system under ambient conditions normally associated with cone system activity. Two GUCY2D-LCA patients demonstrated remnant cone vision but at a luminance level 2 log brighter than normal.
  
  
  CONCLUSIONS
  The newly developed device can probe the existence or emergence of cone-based vision in patients for an orientation task involving the identification of a door on the wall under free-viewing conditions. This key advance represents progress toward developing an appropriate outcome measure for a clinical trial to treat currently incurable eye diseases severely affecting cone vision despite retained rod vision.
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, 51 North 39th St., Philadelphia, PA, 19104, USA. aroman@mail.med.upenn.edu.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, 51 North 39th St., Philadelphia, PA, 19104, USA. cideciya@mail.med.upenn.edu.
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, 51 North 39th St., Philadelphia, PA, 19104, USA. Rodrigo.MatsuiSerrano@uphs.upenn.edu.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Matsui
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, 51 North 39th St., Philadelphia, PA, 19104, USA. Rebecca.Sheplock@uphs.upenn.edu.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sheplock
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, 51 North 39th St., Philadelphia, PA, 19104, USA. Sharon.wolfe@uphs.upenn.edu.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.affiliation: Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, 51 North 39th St., Philadelphia, PA, 19104, USA. jacobsos@mail.med.upenn.edu.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
mesh_terms: D000293:Adolescent; D002648:Child; D003117:Color Vision Defects / Q000503:physiopathology / Q000628:therapy*; D015350:Contrast Sensitivity / Q000502:physiology*; D003623:Dark Adaptation; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011597:Psychomotor Performance / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology*; D012162:Retinal Degeneration / Q000503:physiopathology / Q000628:therapy*; D017948:Retinal Rod Photoreceptor Cells / Q000502:physiology; D014792:Visual Acuity / Q000502:physiology; D057488:Visual Prosthesis
chemical_list: D011956:Receptors, Cell Surface; C110715:guanylate cyclase 1; D006162:Guanylate Cyclase