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dc.contributor.authorBeard, H.en
dc.contributor.authorChidlow, G.en
dc.contributor.authorNeumann, D.en
dc.contributor.authorNazri, N.en
dc.contributor.authorDouglass, M.en
dc.contributor.authorTrim, P.J.en
dc.contributor.authorSnel, M.F.en
dc.contributor.authorCasson, R.J.en
dc.contributor.authorHemsley, K.M.en
dc.identifier.citationActa Neuropathologica Communications, 2020; 8(1):194-1-194-16en
dc.descriptionPublished online: 17 November 2020en
dc.description.abstractSanfilippo syndrome is an untreatable form of childhood-onset dementia. Whilst several therapeutic strategies are being evaluated in human clinical trials including i.v. delivery of AAV9-based gene therapy, an urgent unmet need is the availability of non-invasive, quantitative measures of neurodegeneration. We hypothesise that as part of the central nervous system, the retina may provide a window through which to 'visualise' degenerative lesions in brain and amelioration of them following treatment. This is reliant on the age of onset and the rate of disease progression being equivalent in retina and brain. For the first time we have assessed in parallel, the nature, age of onset and rate of retinal and brain degeneration in a mouse model of Sanfilippo syndrome. Significant accumulation of heparan sulphate and expansion of the endo/lysosomal system was observed in both retina and brain pre-symptomatically (by 3 weeks of age). Robust and early activation of micro- and macroglia was also observed in both tissues. There was substantial thinning of retina and loss of rod and cone photoreceptors by ~ 12 weeks of age, a time at which cognitive symptoms are noted. Intravenous delivery of a clinically relevant AAV9-human sulphamidase vector to neonatal mice prevented disease lesion appearance in retina and most areas of brain when assessed 6 weeks later. Collectively, the findings highlight the previously unrecognised early and significant involvement of retina in the Sanfilippo disease process, lesions that are preventable by neonatal treatment with AAV9-sulphamidase. Critically, our data demonstrate for the first time that the advancement of retinal disease parallels that occurring in brain in Sanfilippo syndrome, thus retina may provide an easily accessible neural tissue via which brain disease development and its amelioration with treatment can be monitored.en
dc.description.statementofresponsibilityHelen Beard, Glyn Chidlow, Daniel Neumann, Nazzmer Nazri, Meghan Douglass, Paul J. Trim, Marten F. Snel, Robert J. Casson and Kim M. Hemsleyen
dc.publisherBioMed Centralen
dc.rights© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.en
dc.subjectRetina; Mucopolysaccharidosis type III; Central nervous system; Eye; Lysosomalen
dc.titleIs the eye a window to the brain in Sanfilippo syndrome?en
dc.typeJournal articleen
dc.identifier.orcidChidlow, G. [0000-0001-7371-0239]en
dc.identifier.orcidNazri, N. [0000-0002-9598-3585]en
dc.identifier.orcidTrim, P.J. [0000-0001-8734-3433]en
dc.identifier.orcidSnel, M.F. [0000-0002-8502-7274]en
dc.identifier.orcidCasson, R.J. [0000-0003-2822-4076]en
dc.identifier.orcidHemsley, K.M. [0000-0003-1038-9884]en
Appears in Collections:Opthalmology & Visual Sciences publications

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