title: Defining Outcomes for Clinical Trials of Leber Congenital Amaurosis Caused by GUCY2D Mutations.
abstract: OBJECTIVE
  To determine outcome measures for a clinical trial of Leber congenital amaurosis (LCA) associated with mutations in the GUCY2D gene.
  
  
  METHODS
  Retrospective observational case series.
  
  
  METHODS
  Twenty-eight patients with GUCY2D-LCA (aged 2-59 years) were studied clinically and with chromatic full-field sensitivity testing (FST), optical coherence tomography (OCT), pupillometry, and the NEI Visual Function Questionnaire (VFQ).
  
  
  RESULTS
  FST permitted quantitation of cone and rod sensitivity in these patients with severe visual impairment. For most patients, the degree of rod and cone sensitivity losses showed a relationship, thereby providing an opportunity to divide patients into cohorts by severity of rod and cone dysfunction. OCT analyses indicated that retinal structure could be used not only as an objective safety measure but also as an exploratory efficacy outcome. A foveal bulge was not present in 67% of patients. The intensity of inner segment/outer segment (ellipsoid zone line) reflectivity was reduced significantly at the fovea and in the rod-dense superior retina. Based on OCT and FST parameters, most patients had dissociation of structure and function. Abnormal pupillometry sensitivity in the majority of GUCY2D-LCA patients provided another objective efficacy outcome. NEI VFQ scores showed a similar range of findings to those of other severe retinal diseases.
  
  
  CONCLUSIONS
  Conventional outcome measures, such as visual acuity and the NEI VFQ, will need to be complemented by methods more specific to this GUCY2D-LCA population. Any therapeutic strategy should determine if there is an effect on rod as well as cone function and structure. FST provides a photoreceptor-based subjective outcome; and OCT in 2 retinal regions, fovea and superior retina, can assess photoreceptor structure. A change in the relationship of structure and function away from baseline becomes evidence of efficacy.
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: jacobsos@mail.med.upenn.edu.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jason
authors.initials: J
authors.lastname: Charng
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Monica
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Shreyasi
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.affiliation: Department of Ophthalmology and Vision Sciences, Program of Genetics and Genomic Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elise
authors.initials: E
authors.lastname: Heon
authors.affiliation: Pangere Center for Hereditary Retinal Diseases, The Chicago Lighthouse, Chicago, Illinois.
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Fishman
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Boye
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D004247:DNA / Q000235:genetics; D004596:Electroretinography; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D012374:Rod Cell Outer Segment / Q000378:metabolism / Q000473:pathology*; D011795:Surveys and Questionnaires; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D055815:Young Adult
chemical_list: D011956:Receptors, Cell Surface; C110715:guanylate cyclase 1; D004247:DNA; D006162:Guanylate Cyclase