Sanfilippo syndrome is a form of childhood dementia that currently has no approved treatment or cure. To better understand Sanfilippo and identify potential therapeutic avenues, researchers can use model organisms like zebrafish to mimic the disease found in humans. 

With an Incubator Grant awarded by the Sanfilippo Children’s Foundation, along with a grant from the Carthew Family Charity Trust, Assoc. Prof. Lardelli will create three new Sanfilippo zebrafish models: one for each of the subtypes A, B and C. Once the zebrafish are developed, they will undergo behavioural testing to examine their cognition. 

Then, through the use of powerful genetic techniques, Assoc. Prof. Lardelli and his team will analyse which other genes are turned on and off in the brains of the Sanfilippo zebrafish. This genetic analysis may provide clues on disease mechanisms or new pathways for therapeutic intervention. In the future, the zebrafish could also be used to test emerging Sanfilippo therapies on the road towards a clinical trial.

Assoc. Prof. Lardelli has significant experience using zebrafish to study an inherited early-onset form of Alzheimer’s disease, which occurs before the age of 65. Using these Alzheimer’s zebrafish models, he has found that disrupted iron absorption may contribute to neurodegeneration. Now, he will translate knowledge gained from his Alzheimer’s studies into the Sanfilippo realm, including whether iron absorption may also contribute to Sanfilippo symptoms.

These new zebrafish will serve as additional tools for researchers to study Sanfilippo and explore potential treatments. We are very excited for Michael to join the Sanfilippo research community and apply his expertise in Alzheimer’s to further Sanfilippo research.

“Through a collaborative, united effort between these fields, we hope to develop a greater understanding of the dementias as a whole, which can be used to identify new therapies,” said Founder and Director of the foundation, Megan Donnell.

Project Update 

Associate Professor Michael Lardelli has completed his Incubator grant awarded in 2020 from the Sanfilippo Children’s Foundation. In this project, A/Prof Lardelli, Dr Karissa Barthelson and Ewan Gerken aimed to develop three new zebrafish models of Sanfilippo, one each for type A, B, and C, and compare these model fish to unaffected zebrafish using behavioural and gene activity tests.

The team successfully developed the three models using a genetic editing technology called CRISPR. They confirmed that each model developed a significant build-up of heparan sulfate when measured at 6 months of age, as would be expected in Sanfilippo syndrome. 

For the behavioural and molecular biology experiments, both the fish with Sanfilippo and the unaffected zebrafish were all from the same family and raised in the same tank. This methodology helps to reduce genetic and environmental differences that, otherwise can obscure results. Each fish only underwent genetic testing to determine its model status (i.e. Sanfilippo or unaffected) after all the behavioural tests were completed. This ensured there was no “observer bias” when collecting the behavioural data.

The team tested the zebrafish’s spatial working memory; that is, how well the fish remember locations they’ve visited and their spatial awareness. However, unlike what would be expected in children affected by Sanfilippo, the team found no significant differences with this test. They plan to repeat these memory experiments using a new, high-throughput technique to confirm their results.

The team then collected the zebrafish brains to conduct a detailed analysis of all the genes that were switched on or off in the Sanfilippo brains compared to the unaffected fish. This type of analysis, known as ‘transcriptomics’, can provide detailed insights into the molecular mechanisms at play in the tissues affected by disease.

The team have now processed this huge amount of data. One of the most significant findings from this work was that the cells producing myelin in the brain (the “insulation” that is wrapped around the brain’s “wires” – axons - to help nerve cells send signals to each other) were very significantly affected compared to other types of brain cell in all three Sanfilippo models, A, B, and C. The team suggest that the large surface area of the myelin producing cells and hence the large areas of scaffolding on the outside of the cells that contains heparan sulfate may play a role in their susceptibility to damage in this condition.

Dr Karissa Barthelesson will continue to investigate what additional information the transcriptome data can reveal with the support of additional funding from a prestigious fellowship from Dementia Australia and Race Against Dementia, and a co-funded grant from The Brain Foundation and Sanfilippo Children’s Foundation. She will be seeking to identify the common biological pathways involved in both adult dementia and Sanfilippo syndrome to see if this might reveal new avenues for treatment for these complex but related conditions.  

Their initial analysis so far reveals important clues about differences in particular brain cell types and important metabolic pathways in the brain. 

The team will be exploring some of these findings through additional funding from the Sanfilippo Children’s Foundation, including an Incubator grant co-funded with the H.A.N.D.S consortium to A/Prof Lardelli for work in a fruit fly model of the disease, and a PhD top-up scholarship awarded to Ewan Gerken to compare zebrafish models of Sanfilippo with early onset Alzheimer’s disease.

The team have presented their initial findings at meetings and symposia around Australia and is working to publish their findings in a scientific journal for other researchers in the field. A pre-publication manuscript can be viewed at the bioRxiv server (https://www.biorxiv.org/content/10.1101/2023.08.02.550904v2).

Assoc. Prof. Michael Lardelli has over 30 years of experience as a geneticist, with the last 18 of those involved in Alzheimer’s Disease research. His laboratory at the University of Adelaide is the world’s leading laboratory using zebrafish to investigate Alzheimer’s Disease. Throughout his career, he has used model organisms and cutting edge genetic techniques to answer key questions about human diseases. 

• Project title: Intra-family analysis of behaviour and brain transcriptomes of MPS IIIA, B, & C model zebrafish
• Chief investigator: Assoc. Prof. Michael Lardelli 
• Amount: $90,000
• Duration: 1 year 
• Location: The University of Adelaide
• Status: Completed
• Start date: January 2021

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