Long-term progression of retinal degeneration in a preclinical model of CLN7 Batten disease as a baseline for testing clinical therapeutics.

Autor:	Rowe AA; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Chen X; Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Nettesheim ER; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Issioui Y; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Dong T; Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Hu Y; Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Messahel S; Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Kayani SN; Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Neurology, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Children's Health, Children's Medical Center, Dallas, TX, 75390, USA., Gray SJ; Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Neurology, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX, 75390, USA; McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Wert KJ; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, 75390, USA; Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX, 75390, USA. Electronic address: Katherine.Wert@UTSouthwestern.edu.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2022 Nov; Vol. 85, pp. 104314. Date of Electronic Publication: 2022 Oct 29.
DOI:	10.1016/j.ebiom.2022.104314
Abstrakt:	Background: Batten disease is characterized by cognitive and motor impairment, retinal degeneration, and seizures leading to premature death. Recent studies have shown efficacy for a gene therapy approach for CLN7 Batten disease. This gene therapy approach is promising to treat cognitive and motor impairment, but is not likely to delay vision loss. Additionally, the natural progression of retinal degeneration in CLN7 Batten disease patients is not well-known. Methods: We performed visual examinations on five patients with CLN7 Batten disease and found that patients were far progressed in degeneration within their first five years of life. To better understand the disease progression, we characterized the retina of a preclinical mouse model of CLN7 Batten disease, through the age at which mice present with paralysis and premature death. Findings: We found that this preclinical model shows signs of photoreceptor to bipolar synaptic defects early, and displays rod-cone dystrophy with late loss of bipolar cells. This vision loss could be followed not only via histology, but using clinical live imaging similar to that used in human patients. Interpretation: Natural history studies of rare paediatric neurodegenerative conditions are complicated by the rapid degeneration and limited availability of patients. Characterization of degeneration in the preclinical model allows for future experiments to better understand the mechanisms underlying the retinal disease progression in order to find therapeutics to treat patients, as well as to evaluate these therapeutic options for future human clinical trials. Funding: Van Sickle Family Foundation Inc., NIHP30EY030413, Morton Fichtenbaum Charitable Trust and 5T32GM131945-03. Competing Interests: Declaration of interests Ms. Rowe has nothing to disclose. Dr. Chen has nothing to disclose. Ms. Nettesheim has nothing to disclose. Mr..ßIssioui has nothing to disclose. Dr. Dong has nothing to disclose. Ms. Hu has nothing to disclose. Dr. Messahel has nothing to disclose. Dr. Kayani has nothing to disclose. Dr. Gray has nothing to disclose. Dr. Wert has nothing to disclose. (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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