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Gene Therapy Targeting the Inner Retina Rescues the Retinal Phenotype in a Mouse Model of CLN3 Batten Disease

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Sophia Martha Kleine Holthaus, Mikel Aristorena, Ryea Maswood, Olha Semenyuk, Justin Hoke, Aura Hare, Alexander J. Smith, Sara E. Mole, Robin R. Ali

Original languageEnglish
Pages (from-to)709-718
Number of pages10
JournalHuman Gene Therapy
Volume31
Issue number13-14
DOIs
Published1 Jul 2020

Bibliographical note

Funding Information: This project was supported by the Batten Disease Family Association, charity No. 1084908, the European Union’s Horizon 2020 research and innovation programme (Grant No. 66691), RP Fighting Blindness (Grant No. GR576), and Medical Research Council (Grant No. MR/R025134/1). R.R.A. is partially supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology. Funding Information: This project was supported by the Batten Disease Family Association, charity No. 1084908, the European Union's Horizon 2020 research and innovation programme (Grant No. 66691), RP Fighting Blindness (Grant No. GR576), and Medical Research Council (Grant No. MR/R025134/1). R.R.A. is partially supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology. Publisher Copyright: © Copyright 2020, by Mary Ann Liebert, Inc., publishers 2020. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

King's Authors

Abstract

The neuronal ceroid lipofuscinoses (NCLs), often referred to as Batten disease, are inherited lysosomal storage disorders that represent the most common neurodegeneration during childhood. Symptoms include seizures, vision loss, motor and cognitive decline, and premature death. The development of brain-directed treatments for NCLs has made noteworthy progress in recent years. Clinical trials are currently ongoing or planned for different forms of the disease. Despite these promising advances, it is unlikely that therapeutic interventions targeting the brain will prevent loss of vision in patients as retinal cells remain untreated and will continue to degenerate. Here, we demonstrate that Cln3Δex7/8 mice, a mouse model of CLN3 Batten disease with juvenile onset, suffer from a decline in inner retinal function resulting from the death of rod bipolar cells, interneurons vital for signal transmission from photoreceptors to ganglion cells in the retina. We also show that this ocular phenotype can be treated by adeno-associated virus (AAV)-mediated expression of CLN3 in cells of the inner retina, leading to significant survival of bipolar cells and preserved retinal function. In contrast, the treatment of photoreceptors, which are lost in patients at late disease stages, was not therapeutic in Cln3Δex7/8 mice, underlining the notion that CLN3 disease is primarily a disease of the inner retina with secondary changes in the outer retina. These data indicate that bipolar cells play a central role in this disease and identify this cell type as an important target for ocular AAV-based gene therapies for CLN3 disease.

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