Targeting Purinergic Signalling in the Brain to Reduce Inflammation in Sanfilippo

The Sanfilippo Children’s Foundation has awarded funds to Associate Professor Kim Hemsley (Flinders University) who, in collaboration with Dr Louise O’Keefe (The University of Adelaide) and Associate Professor Vito Ferro (The University of Queensland), will investigate the potential link between purinergic signalling and inflammation in the brain in Sanfilippo.

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,” said CEO of the Sanfilippo Children’s Foundation, Victoria Bowring. 

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: Active
  •   Start date: March 2021

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