The childhood dementia Sanfilippo syndrome is a complex disease that leads to progressive neurodegeneration. There is mounting evidence that neuroinflammation contributes to the disease symptoms and progression in Sanfilippo syndrome and other neurodegenerative diseases. Anti-inflammatory therapies are thus a growing research area for the disease, with the hope of slowing down the disease or easing symptoms.

Recently, a molecule called C381 was shown to reduce brain inflammation and neurodegeneration in mouse models for Parkinson’s disease and Batten disease. The latter, like Sanfilippo syndrome, is a lysosomal storage disorder that causes childhood dementia. In the two models, C381 was also shown to improve the function of the lysosomes, the compartments inside cells that help to degrade harmful material and recycle waste products.

With the funds from this grant, the team hopes to increase lysosomal activity and reduce neuroinflammation using C381 in a mouse model of Sanfilippo syndrome type A. Although a type A mouse model will be used, the results from this study could likely be transferable to other subtypes of Sanfilippo syndrome.

The team will determine whether C381 can reduce neuroinflammation and neurodegeneration in mice with Sanfilippo. They will take an in-depth look at how C381 affects lysosomes and neuroinflammation by breaking down the key molecular steps involved in the process. In particular, they will investigate a family of gene modulators that are known to be involved in lysosome function and neuroinflammation.

“Anti-neuroinflammatory therapies represent one emerging therapeutic avenue for Sanfilippo and many other neurodegenerative diseases,” said Dr Lisa Melton, Head of Research at the Sanfilippo Children’s Foundation. “This project could open up a potential new therapy option for Sanfilippo that has already shown promise in other similar diseases.” 

Project Update

Dr. Johannes Schlachetzki and his team have completed their Incubator project co-funded by Sanfilippo Children’s Foundation and Fondation Sanfilippo Suisse. 

In this project, Assistant Professor Dr. Schlachetzki and the project team at UCSD, including Associate Professor Dr. Philip Gordts and PhD Candidate Christopher Balak, profiled microglia, immune cells of the brain, in Sanfilippo and tested a compound called C381 to improve their lysosomal function.

Microglia are important for healthy brain function, but they can also help drive inflammation in the brain in Sanfilippo. Using a mouse model of Sanfilippo type A, the team measured which genes in the microglia are turned on and off and investigated key molecular pathways involved in inflammation driven by microglia. Through this, they have identified new drug targets that can be explored further. Specifically, they nominated a transcription factor family called MiT/TFE, which is implicated in lysosomal biogenesis, to be involved in the disease process.

They also tested the small-molecule drug C381, previously developed by Dr. Tony Wyss-Coray (Stanford University). This drug has shown promise for Parkinson’s disease and neuronal ceroid lipofuscinosis, another lysosomal storage disorder. The team found that C381 could work on microglia in mice with Sanfilippo type A to reduce inflammation and improve the function of lysosomes. They will continue to collect and analyse behavioural data from the mouse model and further examine C381’s potential in Sanfilippo, including Sanfilippo type C.

Dr. Schlachetzki presented some of the findings virtually at the 2024 Solving Sanfilippo Symposium, and the team has submitted a manuscript to share the initial results with the research community. Due to this project, Dr. Schlachetzki has forged new collaborations and hopes to start researching additional subtype(s) of Sanfilippo to further understand the impact on microglia and potential therapy options.

Dr Johannes Schlachetzki is a clinical neurologist and researcher whose work centres on the brain immune response and how it can be therapeutically targeted to treat neurological diseases like Alzheimer’s, Parkinson’s, and lysosomal storage disorders.

Project Summary

• Project title: Boosting lysosomal function and targeting neuroinflammation using a small compound for the treatment of Sanfilippo syndrome
• Chief investigator: Dr Johannes Schlachetzki
• Amount: $50,000 from Sanfilippo Children’s Foundation and $50,000 from Fondation Sanfilippo Suisse
• Duration: 1 year
• Location: University of California San Diego
• Status: Completed
• Start date: January 2023

* Type A will be studied in this project, but findings may be applied to all types of Sanfilippo

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