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.”

Project Update 

Dr Elvira De Leonibus and her team, which includes post-doctoral scientist Dr Maria De Risi, have completed their project supported by a grant made in 2021 from Cure Sanfilippo Foundation (USA), Sanfilippo Fighters (Italy), and Sanfilippo Children’s Foundation.

First, the team tested two drugs that act in different ways on the dopamine system, to see which can best address behavioural symptoms without adverse side effects. They tested both drugs in 2-month-old Sanfilippo type A mice and performed behavioural experiments to measure autism-like symptoms in the mice. They found both drugs were able to improve autism-like symptoms compared to untreated mice; however, one of the drugs appeared to increase catalepsy symptoms in the Sanfilippo mice. This is a potential unwanted side-effect that can appear as rigidity of the body and loss of muscle control. 

The other drug improved autism-like symptoms without increasing catalepsy symptoms. Biochemical tests using this second drug also indicated that it helped to restore the levels of dopamine receptor activation in the brain to normal levels. Following seven months of treatment with the second drug, Sanfilippo type A mice showed no adverse effects on muscular and memory impairment.

The team also investigated how the altered metabolism of heparan sulfate (HS) affects brain development in Sanfilippo. HS normally plays a role in both the structure, or scaffolding, in the brain as well as assisting in signalling between brain cells to support growth. Partially degraded HS which builds up in Sanfilippo due to an enzyme deficiency could therefore disrupt these normal processes. By looking at the HS in the brains of mice with and without Sanfilippo type A at birth, and at 2 months and 8 months of age, they saw differences in the structure and function of HS in the Sanfilippo samples over time. This work indicates that Sanfilippo not only increases the amount of HS by-products but also affects the structure and function of HS in the brain, including the function of HS in important brain development pathways and its interaction with proteins that can clump together and are associated with adult-onset dementias. 

The team are working on a manuscript to share their results with the research community. Their data advances the field with a greater understanding of the impacts of HS structure and function. The work in this project may also assist in developing a clinical trial to investigate drugs that can best target the behavioural symptoms in Sanfilippo.

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 Summary

•  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 

View all funded projects