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Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the CEP290 Gene.
Invest Ophthalmol Vis Sci 2017; 58(5):2609-2622IO

Abstract

Purpose

To determine efficacy outcome measures for clinical trials of Leber congenital amaurosis (LCA) associated with a common intronic mutation in the CEP290 gene.

Methods

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.

Results

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.

Conclusions

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.

Authors+Show Affiliations

Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.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.Pangere Center for Hereditary Retinal Diseases, The Chicago Lighthouse, Chicago, Illinois, United States.

Pub Type(s)

Journal Article
Observational Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28510626

Citation

Jacobson, Samuel G., et al. "Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused By the Intronic Mutation in the CEP290 Gene." Investigative Ophthalmology & Visual Science, vol. 58, no. 5, 2017, pp. 2609-2622.
Jacobson SG, Cideciyan AV, Sumaroka A, et al. Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the CEP290 Gene. Invest Ophthalmol Vis Sci. 2017;58(5):2609-2622.
Jacobson, S. G., Cideciyan, A. V., Sumaroka, A., Roman, A. J., Charng, J., Lu, M., ... Fishman, G. A. (2017). Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the CEP290 Gene. Investigative Ophthalmology & Visual Science, 58(5), pp. 2609-2622. doi:10.1167/iovs.17-21560.
Jacobson SG, et al. Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused By the Intronic Mutation in the CEP290 Gene. Invest Ophthalmol Vis Sci. 2017 05 1;58(5):2609-2622. PubMed PMID: 28510626.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Outcome Measures for Clinical Trials of Leber Congenital Amaurosis Caused by the Intronic Mutation in the CEP290 Gene. AU - Jacobson,Samuel G, AU - Cideciyan,Artur V, AU - Sumaroka,Alexander, AU - Roman,Alejandro J, AU - Charng,Jason, AU - Lu,Monica, AU - Choi,Windy, AU - Sheplock,Rebecca, AU - Swider,Malgorzata, AU - Kosyk,Mychajlo S, AU - Schwartz,Sharon B, AU - Stone,Edwin M, AU - Fishman,Gerald A, PY - 2017/5/17/entrez PY - 2017/5/17/pubmed PY - 2017/7/20/medline SP - 2609 EP - 2622 JF - Investigative ophthalmology & visual science JO - Invest. Ophthalmol. Vis. Sci. VL - 58 IS - 5 N2 - Purpose: To determine efficacy outcome measures for clinical trials of Leber congenital amaurosis (LCA) associated with a common intronic mutation in the CEP290 gene. Methods: 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. Results: 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. Conclusions: 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. SN - 1552-5783 UR - https://www.unboundmedicine.com/medline/citation/28510626/Outcome_Measures_for_Clinical_Trials_of_Leber_Congenital_Amaurosis_Caused_by_the_Intronic_Mutation_in_the_CEP290_Gene_ L2 - http://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.17-21560 DB - PRIME DP - Unbound Medicine ER -