Abstract
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.
Highlights
The temporal course of neurodegeneration in Sanfilippo syndrome or mucopolysaccharidosis type IIIA (MPS IIIA) is manifest by a normal infancy followed by progressive intellectual disability in early childhood and death at a median age of 18 years [43]
transferase dUTP nick end labelling (TUNEL)-positive, presumptively apoptosing cells were observed in the MPS IIIA mouse outer nuclear layer (ONL), from 6 weeks of age with the peak period occurring around 12 weeks of age. (Fig. 1k–m)
Our objective is to provide a therapeutic monitoring strategy in addition to a prognostic tool, for children diagnosed with this devastating disorder
Summary
The temporal course of neurodegeneration in Sanfilippo syndrome or mucopolysaccharidosis type IIIA (MPS IIIA) is manifest by a normal infancy followed by progressive intellectual disability in early childhood and death at a median age of 18 years [43]. The most common of four subtypes of Sanfilippo syndrome in Australia [28], MPS IIIA results from an inherited, recessive mutation in the Sanfilippo syndrome is presently untreatable, several therapeutic approaches are under clinical evaluation in patients including but not limited to gene replacement [11, 19, 40]. The monitoring of both disease progression and therapeutic efficacy remains a significant obstacle and there is an urgent unmet need for. Coupled with the observation that retinal dysfunction is a common symptom in cognitively normal patients with later-onset MPS IIIA [29], these findings suggest that the retina requires a high level of lysosomal enzymes for normal function
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