Sanfilippo 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.

中文翻译：

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眼睛是 Sanfilippo 综合征大脑的窗口吗？

Sanfilippo 综合征是一种无法治愈的儿童期痴呆症。虽然在人体临床试验中正在评估几种治疗策略，包括基于 AAV9 的基因治疗的静脉注射，但一个紧迫的未满足需求是非侵入性的、定量的神经变性措施的可用性。我们假设，作为中枢神经系统的一部分，视网膜可以提供一个窗口，通过它可以“可视化”大脑中的退行性病变并在治疗后改善它们。这取决于发病年龄和疾病进展速度在视网膜和大脑中相等。我们首次同时评估了 Sanfilippo 综合征小鼠模型中视网膜和脑退化的性质、发病年龄和速率。在出现症状前（到 3 周龄），在视网膜和大脑中均观察到硫酸乙酰肝素的显着积累和内/溶酶体系统的扩张。在两种组织中也观察到微胶质细胞和巨胶质细胞的稳健和早期激活。到 12 周大时，视网膜显着变薄，杆状和锥状光感受器丢失，此时会出现认知症状。6 周后评估时，向新生小鼠静脉注射临床相关的 AAV9-人磺胺酶载体可防止视网膜和大部分大脑区域出现疾病病变。总的来说，这些发现突出了以前未被认识到的视网膜在 Sanfilippo 疾病过程中的早期和显着参与，这些病变可以通过新生儿用 AAV9-磺胺酶治疗来预防。关键的是，