Exploring the role of heparan sulfate and dopamine as disease modifiers in Sanfilippo

October 18, 2021

Grant Summary

Institution: Telethon Institute of Genetic Medicine (TIGEM), Pozzouli, Italy

Principal Investigator: Elvira De Leonibus, PhD, of TIGEM and the Italian National Research Council

Duration: 24 months

Start Date: July 1, 2021

Type of Sanfilippo studied: A

Types of Sanfilippo to which findings could apply: A, B, C, and D

Research Stage: Translational

Grant Description

Cure Sanfilippo Foundation is collaborating with Sanfilippo Fighters (Italy) and Sanfilippo Children’s Foundation (Australia) on a research grant to Elvira De Leonibus, PhD, together with post-doc Maria De Risi of Telethon Institute of Genetic Medicine (TIGEM) in Italy to further explore the role of heparan sulfate and dopamine as disease modifiers in Sanfilippo syndrome Type A, also known as Mucopolysaccharidosis (MPS) IIIA.

Sanfilippo Type A occurs because of various mutations of the gene that codifies sulfamidase, a lysosomal enzyme that degrades the glycosaminoglycan (GAG) heparan sulfate. Without clearing of heparan sulfate from the cell, it accumulates and progressively engulfs and damages the cell’s ability to degrade all waste. This leads to an accumulation of secondary storages of misfolded proteins, including those that result in neurodegenerative disorders.

Heparan sulfate is a sulfated polysaccharide that has many physiological functions in the brain. It acts as a co-receptor of many growth factors, which are important during brain development and in the trophic maintenance of neurons during the adult life. Previous studies have shown a loss of function of heparan sulfate in Sanfilippo syndrome; however, a lysosome-centric view of Sanfilippo Type A has limited the exploration of all of heparan sulfate’s functional consequences in the cell.

Previous research by Dr. De Leonibus’s group, funded by Cure Sanfilippo Foundation and Sanfilippo Children’s Foundation, found there is an increased proliferation of dopaminergic cells in Sanfilippo Type A during embryonic neurodevelopment, which is not due to a loss of lysosomal function, but rather a loss of heparan sulfate function. It also found that autistic-like symptoms in MPS IIIA mice can be corrected by D1-like receptor antagonistic drugs or D2-like agonist drugs. These are therapeutic alternatives to D2-like antagonist drugs (e.g. risperidone and haloperidol) that have been reported to have side effects in patients with Sanfilippo Type A.

Encouraged by Dr. De Leonibus’ novel and promising preliminary findings, this project seeks to dissect the role of altered heparan sulfate in all stages of Sanfilippo Type A disease course.

Dr. Leonibus’ collaboration with Dr. Dulce Papy-Garcia, a leader in the field of heparan sulfate-signaling, on this project is a key aspect of the research and will further strengthen the team’s ability to understand the varied impacts of altered heparan sulfate signaling in Sanfilippo.

This research also hopes to deepen the pre-clinical study of dopaminergic drugs in pursuit of finding the best candidate for children with Sanfilippo Type A. We expect that these findings would be readily translatable to all types of Sanfilippo.

This is the first time dopaminergic D1 antagonists have been tested as a chronic treatment in the Sanfilippo Type A (MPS IIIA) animal model. The dopaminergic drugs being tested are already used for other diseases. If the proposed treatments are effective, the project will have direct clinical transferability for Sanfilippo Type A patients.

The project’s goals are to bring forward novel symptomatic treatments for Sanfilippo Type A, as well as novel disease modifiers that slow down neurodegeneration and dementia in the children.

“We are pleased to provide continued support to Dr. Leonibus’ innovative work to uncover new disease mechanisms and treatment targets with the potential to benefit children in the near term,” said Dr. Cara O’Neill, Chief Science Officer for Cure Sanfilippo.


Elvira De Leonibus, PhD, and post-doc Maria De Risi of Telethon Institute of Genetic Medicine (TIGEM)

Pictured: Dr. De Leonibus, PhD, together with the post-doc Maria De Risi of Telethon Institute of Genetic Medicine (TIGEM)

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