title: Genotype-dependent variability in residual cone structure in achromatopsia: toward developing metrics for assessing cone health.
abstract: OBJECTIVE
  Gene therapy trials for inherited photoreceptor disorders are planned. Anatomical metrics to select the best candidates and outcomes are needed. Adaptive optics (AO) imaging enables visualization of photoreceptor structure, although analytical tools are lacking. Here we present criteria to assess residual photoreceptor integrity in achromatopsia (ACHM).
  
  
  METHODS
  Two AOSLOs, at the Medical College of Wisconsin and Moorfields Eye Hospital, were used to image the photoreceptor mosaic of 11 subjects with ACHM and 7 age-matched controls. Images were obtained, processed, and montaged using previously described methods. Cone density and reflectivity were quantified to assess residual cone photoreceptor structure.
  
  
  RESULTS
  All subjects with ACHM had reduced numbers of cone photoreceptors, albeit to a variable degree. In addition, the relative cone reflectivity varied greatly. Interestingly, subjects with GNAT2-associated ACHM had the greatest number of residual cones and the reflectivity of those cones was significantly greater than that of the cones in the subjects with CNGA3/CNGB3-associated ACHM.
  
  
  CONCLUSIONS
  We present cone reflectivity as a metric that can be used to characterize cone structure in ACHM. This method may be applicable to subjects with other cone disorders. In ACHM, we hypothesize that cone numerosity (and/or density) combined with cone reflectivity could be used to gauge the therapeutic potential. As gene replacement would not be expected to add cones, reflectivity could be a more powerful AO-metric for monitoring the cellular response to treatment and could provide a more immediate indicator of efficacy than behavioral measures, which may take longer to change.
authors.affiliation: Moorfields Eye Hospital, London, United Kingdom UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Dubis
authors.affiliation: Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin, United States.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Cooper
authors.affiliation: Moorfields Eye Hospital, London, United Kingdom UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Aboshiha
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Langlo
authors.affiliation: Moorfields Eye Hospital, London, United Kingdom UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Venki
authors.initials: V
authors.lastname: Sundaram
authors.affiliation: Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Liu
authors.affiliation: The Pangere Center for Hereditary Retinal Diseases, The Chicago Lighthouse for People Who Are Blind or Visually Impaired, Chicago, Illinois, United States.
authors.forename: Frederick
authors.initials: F
authors.lastname: Collison
authors.affiliation: The Pangere Center for Hereditary Retinal Diseases, The Chicago Lighthouse for People Who Are Blind or Visually Impaired, Chicago, Illinois, United States.
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Fishman
authors.affiliation: Moorfields Eye Hospital, London, United Kingdom UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: Moorfields Eye Hospital, London, United Kingdom UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin, United States Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Dubra
authors.affiliation: Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin, United States Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Carroll
authors.affiliation: Moorfields Eye Hospital, London, United Kingdom UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
mesh_terms: D000328:Adult; D002452:Cell Count; D003117:Color Vision Defects / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009887:Ophthalmoscopy / Q000379:methods*; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D041623:Tomography, Optical Coherence / Q000379:methods*; D014792:Visual Acuity; D055815:Young Adult
keywords: cones; genetic diseases; image analysis