Long-term progression of retinal degeneration in a preclinical model of CLN7 Batten disease as a baseline for testing clinical therapeuticsResearch in context
Ashley A. Rowe,
Xin Chen,
Emily R. Nettesheim,
Yacine Issioui,
Thomas Dong,
Yuhui Hu,
Souad Messahel,
Saima N. Kayani,
Steven J. Gray,
Katherine J. Wert
Affiliations
Ashley A. Rowe
Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, 75390, USA
Xin Chen
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
Emily R. Nettesheim
Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, 75390, USA
Yacine Issioui
Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, 75390, USA
Thomas Dong
Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, 75390, USA
Yuhui Hu
Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, 75390, USA
Souad Messahel
Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, 75390, USA
Saima N. Kayani
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
Steven J. Gray
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
Katherine J. Wert
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; Corresponding author. Departments of Ophthalmology and Molecular Biology, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
Summary: 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., NIH P30EY030413, Morton Fichtenbaum Charitable Trust and 5T32GM131945-03.
