title: Retinal structure and function in achromatopsia: implications for gene therapy.
abstract: OBJECTIVE
  To characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical trials of gene therapy.
  
  
  METHODS
  Cross-sectional study.
  
  
  METHODS
  Forty subjects with ACHM.
  
  
  METHODS
  All subjects underwent spectral domain optical coherence tomography (SD-OCT), microperimetry, and molecular genetic testing. Foveal structure on SD-OCT was graded into 5 distinct categories: (1) continuous inner segment ellipsoid (ISe), (2) ISe disruption, (3) ISe absence, (4) presence of a hyporeflective zone (HRZ), and (5) outer retinal atrophy including retinal pigment epithelial loss. Foveal and outer nuclear layer (ONL) thickness was measured and presence of hypoplasia determined.
  
  
  METHODS
  Photoreceptor appearance on SD-OCT imaging, foveal and ONL thickness, presence of foveal hypoplasia, retinal sensitivity and fixation stability, and association of these parameters with age and genotype.
  
  
  RESULTS
  Forty subjects with a mean age of 24.9 years (range, 6-52 years) were included. Disease-causing variants were found in CNGA3 (n = 18), CNGB3 (n = 15), GNAT2 (n = 4), and PDE6C (n = 1). No variants were found in 2 individuals. In all, 22.5% of subjects had a continuous ISe layer at the fovea, 27.5% had ISe disruption, 20% had an absent ISe layer, 22.5% had an HRZ, and 7.5% had outer retinal atrophy. No significant differences in age (P = 0.77), mean retinal sensitivity (P = 0.21), or fixation stability (P = 0.34) across the 5 SD-OCT categories were evident. No correlation was found between age and foveal thickness (P = 0.84) or between age and foveal ONL thickness (P = 0.12).
  
  
  CONCLUSIONS
  The lack of a clear association of disruption of retinal structure or function in ACHM with age suggests that the window of opportunity for intervention by gene therapy is wider in some individuals than previously indicated. Therefore, the potential benefit for a given subject is likely to be better predicted by specific measurement of photoreceptor structure rather than simply by age. The ability to directly assess cone photoreceptor preservation with SD-OCT and/or adaptive optics imaging is likely to prove invaluable in selecting subjects for future trials and measuring the trials' impact.
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK; Moorfields Eye Hospital, London, UK.
authors.forename: Venki
authors.initials: V
authors.lastname: Sundaram
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Wilde
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK; Moorfields Eye Hospital, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Aboshiha
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Cowing
authors.affiliation: Summer Program for Undergraduate Research, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Colin
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Langlo
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK; Moorfields Eye Hospital, London, UK.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Chana
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK; Moorfields Eye Hospital, London, UK.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Davidson
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.
authors.forename: Panagiotis I
authors.initials: PI
authors.lastname: Sergouniotis
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK; Moorfields Eye Hospital, London, UK.
authors.forename: James W
authors.initials: JW
authors.lastname: Bainbridge
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
authors.affiliation: Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Dubra
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Rubin
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK; Moorfields Eye Hospital, London, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK; Moorfields Eye Hospital, London, UK.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.
authors.forename: Marko
authors.initials: M
authors.lastname: Nardini
authors.affiliation: Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Joseph
authors.initials: J
authors.lastname: Carroll
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK; Moorfields Eye Hospital, London, UK. Electronic address: michel.michaelides@ucl.ac.uk.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003117:Color Vision Defects / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology*; D003430:Cross-Sectional Studies; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D015316:Genetic Therapy; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D012160:Retina / Q000503:physiopathology*; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology; D058609:Visual Field Tests; D014794:Visual Fields / Q000502:physiology; D055815:Young Adult
chemical_list: C518238:CNGA3 protein, human; C415904:CNGB3 protein, human; D054815:Cyclic Nucleotide-Gated Cation Channels; D005136:Eye Proteins; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C096885:PDE6C protein, human; D020962:Heterotrimeric GTP-Binding Proteins