Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the CEP290 Gene

Samuel G Jacobson; Artur V Cideciyan; Alexander Sumaroka; Alejandro J Roman; Jason Charng; Monica Lu; Windy Choi; Rebecca Sheplock; Malgorzata Swider; Mychajlo S Kosyk; Sharon B Schwartz; Edwin M Stone; Gerald A Fishman

doi:10.1167/iovs.17-21560

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Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the CEP290 Gene

Journal article

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Peer reviewed

Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the CEP290 Gene

Samuel G Jacobson, Artur V Cideciyan, Alexander Sumaroka, Alejandro J Roman, Jason Charng, Monica Lu, Windy Choi, Rebecca Sheplock, Malgorzata Swider, Mychajlo S Kosyk, …

Investigative ophthalmology & visual science, Vol.58(5), pp.2609-2622

05/01/2017

DOI: 10.1167/iovs.17-21560

PMID: 28510626

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Abstract

To determine efficacy outcome measures for clinical trials of Leber congenital amaurosis (LCA) associated with a common intronic mutation in the CEP290 gene. CEP290-LCA patients (ages 5-48) with the intronic mutation (c.2991+1655A>G) were studied as a retrospective observational case series using clinical methods and with full-field sensitivity testing (FST), optical coherence tomography (OCT), autofluorescence imaging (NIR-RAFI), transient pupillary light reflex (TPLR), oculomotor control and instability (OCI), a mobility course, and a questionnaire (NEI-VFQ). Patients were investigated cross-sectionally but a subset was able to be followed longitudinally. With FST, there was no rod function; cone sensitivities had a wide range from not detectable to near normal. OCT analyses indicated retained central photoreceptors with abnormal distal laminae. Based on OCT and FST, most patients had dissociation of structure and function. TPLR was nondetectable in the majority of patients, with responders demonstrating severe losses in light sensitivity. OCI was abnormal in most patients. NEI-VFQ scores had a similar range to those of other severe retinopathies. Mobility scores were consistent with FST sensitivities. In patients examined with FST, OCT, and NIR-RAFI over long-term intervals (7-10 years), there was limited but detectable disease progression. Efficacy would be a quantitative change in foveal cone function and possibly distal laminar structure. FST provides a subjective photoreceptor-based outcome; OCT and NIR-RAFI can assess photoreceptor and RPE structure. TPLR and OCI can provide objective measures of postretinal transmission. Minimal change over a decade indicates that there is no practical value in natural history studies.

Outcome Assessment (Health Care)

Humans

Middle Aged

Child, Preschool

Male

Neoplasm Proteins - metabolism

Young Adult

DNA Mutational Analysis

Leber Congenital Amaurosis - metabolism

Retinal Cone Photoreceptor Cells - pathology

Antigens, Neoplasm - metabolism

Adult

Female

Retrospective Studies

Neoplasm Proteins - genetics

Child

Electroretinography

Antigens, Neoplasm - genetics

Clinical Trials as Topic

Leber Congenital Amaurosis - genetics

Tomography, Optical Coherence - methods

DNA - genetics

Adolescent

Leber Congenital Amaurosis - diagnosis

Mutation

Retinal Cone Photoreceptor Cells - metabolism

Details

Title: Subtitle: Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the CEP290 Gene
Creators: Samuel G Jacobson - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Artur V Cideciyan - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Alexander Sumaroka - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Alejandro J Roman - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Jason Charng - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Monica Lu - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Windy Choi - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Rebecca Sheplock - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Malgorzata Swider - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Mychajlo S Kosyk - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Sharon B Schwartz - Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Edwin M Stone - Department of Ophthalmology and Visual Science, Carver College of Medicine, Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, Iowa, United States
Gerald A Fishman - Pangere Center for Hereditary Retinal Diseases, The Chicago Lighthouse, Chicago, Illinois, United States
Resource Type: Journal article
Publication Details: Investigative ophthalmology & visual science, Vol.58(5), pp.2609-2622
DOI: 10.1167/iovs.17-21560
PMID: 28510626
NLM abbreviation: Invest Ophthalmol Vis Sci
ISSN: 0146-0404
eISSN: 1552-5783
Publisher: United States
Language: English
Date published: 05/01/2017
Academic Unit: Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983979991402771

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