Summary: A retinal image technique sheds new light on Sanfilippo syndrome, a neurodegenerative disorder responsible for dementia in children.
Source: Flinders University
Is the eye a window to the brain in Sanfilippo syndrome, an untreatable form of childhood-onset dementia, Australian researchers ask in a new publication.
The findings of the NHMRC-funded project, just published in international journal Acta Neuropathologica Communications, highlight the potential for using widely available retinal imaging techniques to learn more about brain disease and monitor treatment efficacy.
Sanfilippo syndrome is one of a group of about 70 inherited conditions which collectively affect 1 in 2800 children in Australia, and is more common than cystic fibrosis and better known diseases. Around the world 700,000 children and young people are living with childhood dementia.
Researchers from Flinders University, with collaborators at the South Australian Health and Medical Research Institute (SAHMRI) and The University of Adelaide, studied Sanfilippo syndrome in mouse models, discovering for the first time that advancement of retinal disease parallels that occurring in the brain.
“This means the retina may provide an easily accessible neural tissue via which brain disease development and its amelioration with treatment can be monitored,” says Associate Professor Kim Hemsley who leads the Childhood Dementia Research Group at the Flinders Health and Medical Research Institute (FHMRI) at Flinders University.
First author Helen Beard, from the Childhood Dementia Research Group at Flinders University, says there’s an urgent need to find treatments and methods to monitor disease progression.
Disorders that cause childhood dementia are neurodegenerative (debilitating and progressive) and impair mental function, according to the Childhood Dementia Initiative.
“This study offers new hope of using the progression of lesions in the retina – which is part of the central nervous system – as a ‘window to the brain’,” says senior research officer Ms Beard. “We were able to show that disease lesions appear in the retina very early in the disease course, in fact much earlier than previously thought,” she says.
This means that in addition to ensuring potential treatments reach the brain, researchers must also confirm that they get into the retina to give patients maximum quality of life.
“Our findings suggest that retinal imaging may provide a strategy for monitoring therapeutic efficacy, given that some treatments currently being trialled in children with Sanfilippo syndrome are able to access both brain and retina,” Associate Professor Hemsley says.
Therapeutic strategies currently being evaluated in human clinical trials include IV delivery of an AAV9-based gene therapy, and a non-invasive, quantitative measure of neurodegeneration would support development of effective treatments, she says.
Is the eye a window to the brain in Sanfilippo syndrome?
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.