In Sanfilippo syndrome, there is a build-up of the molecule heparan sulfate, which leads to the progressive cognitive decline associated with this childhood dementia. While researchers continue to investigate the mechanism of how heparan sulfate accumulation affects the brain, it is known that loss of neurons occurs relatively late in the disease process. This suggests that other processes may be playing a more significant role in the symptoms of Sanfilippo and there is increasing evidence that inflammation is involved. 

Inflammation in the brain adversely affects the structure of the brain cells, including the synapses that are critical for brain cell communication. As a consequence, there is reduced messaging between brain cells, contributing to the neurological symptoms seen in the disease. 

Purines are one group of molecules involved in brain cell communication via ‘purinergic signalling’. Purines play a role in signalling across the synapses, from neuron to neuron, as well as in activating the inflammatory cells of the brain, known as glia. Associate Professor Kim Hemsley, Dr Louise O’Keefe and colleagues have previously found that purine signalling is altered in Sanfilippo. Now, the team will further investigate potential links between purines, purinergic signalling, brain inflammation and the cognitive symptoms of Sanfilippo. This will be carried out using both mouse and fruit fly Sanfilippo models.

One aspect of the study involves the synthesis and delivery of a small molecule drug to Sanfilippo type A mice. It is hoped that this drug will modify purinergic signalling and improve the symptoms of Sanfilippo. These tests will be performed on both young and older Sanfilippo mice, to see the effect on different stages of the disease. 

Megan Donnell, Founder and Director of the Foundation and mother to two children with Sanfilippo, said: “The drug is still in the early days of development, and further testing is required; however, promising results may pave the way for this class of drugs to be investigated as therapeutic avenues for Sanfilippo and potentially other forms of dementia.”

As part of this project, collaborator Dr Louise O’Keefe will use type A and C fruit fly models to look more closely at the steps involved in purinergic signalling between neurons and between neurons and glia. Dissecting each step will provide a greater understanding of the role of purinergic signalling in Sanfilippo, and will help to determine if any steps can be targeted therapeutically.

The emerging link between brain communication and inflammation demands further investigation with investment in basic research. The results of this study have the potential to influence not just the Sanfilippo field, but dementia research as a whole.

Project update

Professor Kim Hemsley (Flinders University), Professor Vito Ferro (The University of Queensland), and Dr Louise O’Keefe and Dr Sher Li Tan (The University of Adelaide) have completed their Incubator project awarded in 2020. Through the use of mouse and fly models of Sanfilippo, the team investigated if key steps involved in a key cell signalling pathway, involving chemicals called purines, can be targeted in therapy development for Sanfilippo. 

In their project, they studied a drug that targets purinergic signalling in the brain. The drug was made and purified in the laboratory by Professor Vito Ferro and his Medicinal Chemistry team at The University of Queensland. Professor Hemsley then tested it in a mouse model of Sanfilippo type A.

The drug was administered into the brains of mice with and without Sanfilippo via a drug delivery device. Professor Hemsley and Dr Adeline Lau compared the effects of short and long treatment periods and treatment in young or adult mice. They found that, when treatment started at an early age, the drug significantly reduced the number of immune cells in an inflammatory state in the Sanfilippo mouse brain. The longer the treatment period, the greater this reduction in inflammatory cells. However, other markers of inflammation and other features of neurodegeneration in brain cells did not change. 

In a parallel arm of the project, Dr Louise O’Keefe and Dr Sher Li Tan at The University of Adelaide examined the role of purine signalling in a Sanfilippo type A fruit fly model. They developed Sanfilippo type A fruit fly lines that were deficient in key proteins involved in purinergic signalling. Dr Tan found that the Sanfilippo flies that were deficient in one particular protein involved in purine signalling performed worse than the typical Sanfilippo flies in a climbing test. This indicates that the protein may play an important role in Sanfilippo.

Overall, the team’s data in mouse and fruit fly models of Sanfilippo indicate that purinergic signalling plays a role in the disease and therapies targeting this type of signalling can be further explored. The team will continue to investigate the drug and purinergic signalling in different animal models to confirm whether they have potential as treatments for Sanfilippo.

Data from the project have been presented at various conferences in Australia and internationally and will be published when further data has been gathered. 

Assoc. Prof. Kim Hemsley is a seasoned researcher in the Sanfilippo field, interested in deciphering key disease processes in Sanfilippo and evaluating therapy effectiveness. She is the head of the Childhood Dementia Research Group located at Flinders University in Adelaide, Australia. 

Project Summary

•   Project title: Targeting Purinergic Signalling in the Brain to Reduce Inflammation in Sanfilippo
•   Chief investigator: Assoc. Prof. Kim Hemsley
•   Amount: $89,820
•   Duration: 2 years (extension granted)
•   Location: Flinders University 
•   Status: Completed
•   Start date: March 2021

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