Is the eye a window to the brain in Sanfilippo syndrome?

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.

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step towards Understanding and Treating Mucopolysaccharidoses

“…There are, however, teams attempting brain-specific delivery of both ERT and chemical compounds for MPS type III. In general, there are three strategies to increase the delivery (reviewed in [ 20 ]): enzymatic modulation, route(s) of administration [ 21 , 22 , 23 ], and increase in enzyme dosage. In addition, cellular and genetic therapies represent approaches that have gained importance when it comes to BBB delivery (reviewed in [ 24 ]).…”

Biomarkers for predicting disease course in Sanfilippo syndrome: An urgent unmet need in childhood‐onset dementia

“…Optical coherence tomography (OCT) is a tool widely available to the optometrist, which is capable of imaging the structure of the retina and optic nerve non‐invasively. Thinning of the retina's outer nuclear layers correlating with disease progression, and disease prevention by gene therapy in MPS IIIA mice, highlights OCTs' potential in monitoring disease progression and response to treatment (Beard et al, 2020). Findings corroborated in MPS IIIC (Ludwig et al, 2023).…”

Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step Towards Understanding and Treating Mucopolysaccharidoses

“…There are, however teams attempting brain-specific delivery of both ERT and chemical compounds for MPS type III. In general, there are three strategies to increase the delivery (reviewed in [73]): enzymatic modulation, route(s) of administration [74][75][76], and increase of enzyme dosage. In addition, cellular and genetic therapies represent approaches that have gained importance when it comes to BBB delivery (reviewed in [77]).…”