Insight into the role of heparan sulfate and dopamine as disease modifiers in Mucopolysaccharidosis type IIIA

The Sanfilippo Children’s Foundation has partnered with Cure Sanfilippo Foundation (USA) and Sanfilippo Fighters (Italy) to award funds to Dr Elvira De Leonibus at the Telethon Institute of Genetics and Medicine (TIGEM) in Italy. Dr De Leonibus will continue her work on the consequences of altered heparan sulfate metabolism in brain development in Sanfilippo and the use of dopamine drugs for behavioural symptoms.

Sanfilippo is a form of childhood dementia that involves the build-up of a complex sugar called heparan sulfate (HS). As HS accumulates, it affects cell growth and development, impacting all body systems. The brain is severely impacted: patients experience anxiety, hyperactivity and impulsivity, which precede the dementia symptoms.

To address these behaviours, doctors often ‘borrow’ drugs used in other conditions with similar symptoms, like autism and psychosis. Unfortunately, these drugs can have variable results in Sanfilippo; they may not work as well for some Sanfilippo patients and can cause adverse side-effects, like involuntary muscle contractions or tremors.

Previously, Dr De Leonibus has linked the altered development of the dopamine system in the brain with some of the behavioural symptoms of Sanfilippo. The work was supported in part with funding from a 2018 incubator grant from the Sanfilippo Children’s Foundation and Cure Sanfilippo Foundation. 

In this current translational project, Dr De Leonibus and her team, including post-doctoral scientist Dr Maria De Risi, will continue their investigations into the behavioural symptoms of Sanfilippo. The project will explore how HS in Sanfilippo disturbs brain cell growth and development, including the development of the dopamine system. The effects of altered HS structure and function on aspects like cell signalling and protein aggregation will be investigated, using a variety of cellular tests.  

They will also continue to focus on a class of drugs that target the dopamine system in the brain. The team will administer the drugs in type A mice and perform social tests to find the best medicines that improve symptoms while minimising adverse side effects. The effects of chronic treatment and new dose regimens will be examined.

“The behavioural symptoms of Sanfilippo remain some of the most challenging symptoms for not only the individual with Sanfilippo, but their whole family and extended network,” said Victoria Bowring, CEO of the Sanfilippo Children’s Foundation. “This study has the potential to change clinical practice and improve the quality of life for all those affected by Sanfilippo. We are excited to continue to fund this vital research with Cure Sanfilippo Foundation, and to form new funding collaborations with Sanfilippo Fighters.”

Dr De Leonibus is Head of the behavioural core at TIGEM and is Group Leader of the Lab of Neuropsychopharmacology at the Institute of Biochemistry and Cellular Biology. She has been working in the field of lysosomal storage disorders for more than 10 years with the ultimate goal of finding treatments for the behavioural problems in these conditions.

  •  Project title: Insight into the role of heparan sulfate and dopamine as disease modifiers in Mucopolysaccharidosis type IIIA
  • Chief investigators: Dr Elvira De Leonibus
  • Amount: $250,000, with the Sanfilippo Children’s Foundation contributing $50,000, Cure Sanfilippo Foundation (USA) contributing $125,000 and Sanfilippo Fighters (Italy) contributing $75,000
  • Duration: 2 years
  • Location: Telethon Institute of Genetics and Medicine (TIGEM), Italy
  • Status: Active
  • Start date: July 2021 

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