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Prevention of Photoreceptor Cell Loss in a Cln6nclf Mouse Model of Batten Disease Requires CLN6 Gene Transfer to Bipolar Cells

Kleine Holthaus, S-M; Ribeiro, J; Abelleira-Hervas, L; Pearson, RA; Duran, Y; Georgiadis, A; Sampson, RD; ... Ali, RR; + view all (2018) Prevention of Photoreceptor Cell Loss in a Cln6nclf Mouse Model of Batten Disease Requires CLN6 Gene Transfer to Bipolar Cells. Molecular Therapy , 26 (5) pp. 1343-1353. 10.1016/j.ymthe.2018.02.027. Green open access

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Abstract

The neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage disorders characterized by general neurodegeneration and premature death. Sight loss is also a major symptom in NCLs, severely affecting the quality of life of patients, but it is not targeted effectively by brain-directed therapies. Here we set out to explore the therapeutic potential of an ocular gene therapy to treat sight loss in NCL due to a deficiency in the transmembrane protein CLN6. We found that, although Cln6nclfmice presented mainly with photoreceptor degeneration, supplementation of CLN6 in photoreceptors was not beneficial. Because the level of CLN6 is low in photoreceptors but high in bipolar cells (retinal interneurons that are only lost in Cln6-deficient mice at late disease stages), we explored the therapeutic effects of delivering CLN6 to bipolar cells using adeno-associated virus (AAV) serotype 7m8. Bipolar cell-specific expression of CLN6 slowed significantly the loss of photoreceptor function and photoreceptor cells. This study shows that the deficiency of a gene normally expressed in bipolar cells can cause the loss of photoreceptors and that this can be prevented by bipolar cell-directed treatment.

Type: Article
Title: Prevention of Photoreceptor Cell Loss in a Cln6nclf Mouse Model of Batten Disease Requires CLN6 Gene Transfer to Bipolar Cells
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ymthe.2018.02.027
Publisher version: http://dx.doi.org/10.1016/j.ymthe.2018.02.027
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: AAV gene therapy, Batten disease, bipolar cells, lysosomal storage disorders, neuronal ceroid lipofuscinoses, photoreceptors, retina
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10046294
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