OUR FUNDED PROJECTS

Sanfilippo Syndrome is a form of childhood dementia involving the build-up of heparan sulfate, a complex sugar. This build-up is particularly devastating in the brain, where it interferes with key cellular functions and results in neurodegeneration. 

As a result of the build-up of heparan sulfate and the dysfunction it causes, other molecules can also build up over time. One example lies in research published in early 2020 by Assoc. Prof. Fraldi and his colleagues, made possible with funds from the Cure Sanfilippo Foundation. The study found that insoluble aggregates of amyloid proteins, like those found in Alzheimer’s disease, accumulated within the brains of mice with Sanfilippo types A, B and C. Using a type A mouse model, they showed that these amyloid aggregates contribute to cellular dysfunction and neurodegeneration. As the aggregates appear to promote Sanfilippo symptoms, preventing this amyloid aggregation may present a new therapeutic approach for Sanfilippo.

Drugs that can prevent and remove existing amyloid aggregates are sought after in the treatment of Alzheimer’s disease and other dementias involving amyloid aggregation. CLR01 is one candidate molecule that appears to be safe in animals and can cross the blood-brain barrier. Often referred to as a ‘molecular tweezer’, CLR01 can prevent amyloid aggregation and may facilitate its clearance.

In previous research, Assoc. Prof. Fraldi showed that CLR01 could reduce amyloid aggregation and the associated inflammation and dysfunction in young Sanfilippo type A mice. However, when CLR01 was given to older type A mice it could only prevent further aggregation but did not clear existing aggregates, nor did it improve brain inflammation or cellular dysfunction.

Now, in this Translational grant, Assoc. Prof. Fraldi and his colleagues will take this research forward to further investigate the therapeutic potential of CLR01 in Sanfilippo in both young and older mice. CLR01 will be administered to both types B and C mice to see whether there are improvements in aggregation, brain inflammation, cellular dysfunction and mouse behaviour. CLR01 will also be administered to older type A mice again but using a higher dose and longer treatment period. In doing so, there will be a clearer picture of whether CLR01 can improve symptoms at a later stage of the disease. Positive results will strengthen the case for the therapeutic potential of CLR01 for Sanfilippo. 

The researchers will also compare the effects of CLR01 with an AAV9-based gene therapy that is currently in a clinical trial and see whether administering both therapies together can work synergistically to produce a better treatment outcome. 

“We are very excited to partner with Cure Sanfilippo Foundation and the HANDS consortium to fund the next phase of this research and further explore the potential of CLR01 in Sanfilippo,” said CEO of the Sanfilippo Children’s Foundation, Victoria Bowring.

“This work is particularly exciting as it has the potential to improve treatment outcomes for not only Sanfilippo but also move the field forward for other childhood and adult dementias,” said Megan Donnell, Founder and Director of the Foundation.

Associate Professor Alessandro Fraldi’s research focuses on the study of Sanfilippo and other lysosomal storage diseases, and the development of therapies to treat these diseases. His laboratory has developed new AAV-mediated gene therapy approaches, including one that is currently in a clinical trial. 

*The H.A.N.D.S consortium represents eight global non-profit medical research foundations that work together to fund MPS IIIC research

Project Update

Associate Professor Alessandro Fraldi and his team have completed their project supported by a Translational grant awarded in 2020 by Sanfilippo Children’s Foundation, Cure Sanfilippo Foundation (USA), and the H.A.N.D.S. consortium.

The research team had previously shown that abnormal clumps, or aggregates, of amyloid proteins contribute to the death of neurons in Sanfilippo and contribute to symptoms. In preliminary experiments, they were able to show that a small drug molecule, known as CLR01, could reduce amyloid aggregation and neuroinflammation in mice with Sanfilippo type A if they were treated at a young age. In this project, they explored this finding further and confirmed that CLR01 can prevent amyloid accumulation and neuroinflammation in young mice, but found that CLR01 treatment was ineffective if the mice were treated at an older age when disease pathology was more advanced.

Using the Sanfilippo type A mouse model, they also compared the effects of CLR01 treatment alone and when combined with an AAV9-based gene therapy, which is currently in a clinical trial. They found that the combined treatment led to the best results indicating that the CLR01 treatment could be used to enhance the effects of gene therapy treatments for Sanfilippo.

The team also tested CLR01 in mouse models of Sanfilippo types B and C. The treatment was also able to reduce amyloid aggregation and improve symptoms in these mice, confirming that it could be used for multiple forms of Sanfilippo.

Associate Professor Fraldi and his collaborators, including Prof. Gal Bitan and Prof. Thomas Schrader, are continuing to work on the molecule CLR01 in the treatment of Sanfilippo and explore the potential for testing in a clinical trial. The team is also working on publishing their findings in a scientific journal to share the results with the wider scientific community.

Project Summary

• Project title: Strengthening the rationale for the use of the "molecular tweezer” CLR01 in the treatment of Sanfilippo syndrome
• Chief investigator: Assoc. Prof. Alessandro Fraldi
• Amount: AU$579,200 total, with Cure Sanfilippo Foundation contributing US$225,000 and the H.A.N.D.S. consortium contributing €10,000
• Duration: 2 years 
• Location: CEINGE - Advanced Biotechnology, Naples, Italy
• Status: Active
• Start date: March 2021

View all funded projects