Sanfilippo syndrome is caused by a deficiency of one of four enzymes: sulfamidase, NAGLU, HGSNAT, or GNS. This primarily leads to an accumulation of heparan sulfate in the brain and body. Currently, the exact steps that lead from this accumulation of heparan sulfate to cell damage and disease symptoms are not completely understood. 

When researching potential disease mechanisms in Sanfilippo disease, Prof. Pshezhetsky and his team found that another enzyme, called neuraminidase 1 (NEU1), is also deficient in Sanfilippo. They proposed that this ‘secondary deficiency’ of NEU1 is contributing to the Sanfilippo disease process.

NEU1’s role in the body is to remove special sugars, called sialic acids, from proteins that are coated with them. It is an important enzyme: changes in the NEU1 gene leading to a primary deficiency of the NEU1 enzyme result in a disease called sialidosis, a severe lysosomal storage disorder like Sanfilippo. 

When Prof. Pshezhetsky’s team studied a Sanfilippo type C mice model, they also found that their brain contains more sialic acid-coated proteins. These findings were mirrored in post-mortem tissues of patients with Sanfilippo. 

In this project, Prof. Pshezhetsky and his team will investigate this secondary NEU1 deficiency further to confirm whether it contributes to the neurological symptoms of Sanfilippo disease.

First, the team will use mice models to see if NEU1 activity is also reduced in other lysosomal diseases, understand the biological processes leading to this secondary deficiency, and better understand the consequences of increased sialic acid-coated proteins for brain function.

Understanding how Sanfilippo and its symptoms develop is essential for Sanfilippo research and therapy development. Insights gained from this project may inform future therapeutic avenues for Sanfilippo syndrome.

Project Update

Professor Alexey Pshezhetsky and his team have completed their Incubator project investigating whether a secondary deficiency of the enzyme ‘neuraminidase 1’ (NEU1) contributes to the effects of Sanfilippo in the brain. The project was funded by Sanfilippo Children’s Foundation, Fundacja Sanfilippo (Poland), Sanfilippo Initiative (Germany), and the H.A.N.D.S. consortium (Associação Sanfilippo Portugal, Sanfilippo Barcelona, Sanfilippo Sud).

Neuraminidase is a protein that helps metabolise, or breakdown, proteins, by removing chemical groups called sialic acids from the proteins. Previously, the team had identified a NEU1 deficiency in the brain of a Sanfilippo type C mouse model. In this project, they further investigated the levels of NEU1 and other proteins in brain tissue from mouse models of Sanfilippo types A, B and C and other similar MPS diseases. They identified important metabolic processes that are affected in the lysosomes, how the NEU1 deficiency arises in Sanfilippo and how this leads to an unhelpful increase in sialic acid-coated proteins. 

With the support of additional funds from the Canadian Institutes of Health Research, the team used a gene therapy to deliver functional NEU1 in mice with Sanfilippo type C and observed how this affected mice behaviour and pathology in the brain. Their results indicated improvements in memory in the mice. They also observed improvements in the structure and function of brain cells, indicating that a NEU1 deficiency may indeed contribute to the brain pathology seen in Sanfilippo and related conditions and that targeting this deficiency with treatments could be beneficial. 

The project uncovered new insights into the effects of waste accumulation in Sanfilippo that could be used to investigate new therapy avenues. Some of these results have been presented at a conference, and Professor Pshezhetsky and the team are working on publishing their findings in a peer-reviewed journal soon.

Alexey Pshezhetsky is a Professor of paediatrics and biochemistry at the University of Montreal and a researcher at Ste-Justine University Hospital Center (CHUSJ). He has over 25 years of experience researching disease mechanisms and developing treatments for genetic diseases that affect children, including Sanfilippo and particularly Sanfilippo type C.

Project Summary

• Project title: Secondary deficiency of neuraminidase 1 in neurological mucopolysaccharidoses: mechanism and pathological implications
• Chief investigator: Prof. Alexey Pshezhetsky; collaborators: Prof. Domenico Garozzo (Italy) and Prof. Herbert Hildebrandt (Germany) 
• Amount: $27,500 from Sanfilippo Children’s Foundation, $18,750 from Fundacja Sanfilippo (Poland), $18,750 from Sanfilippo Initiative (Germany), and $10,000 from the H.A.N.D.S. consortium (Associação Sanfilippo Portugal, Sanfilippo Barcelona, Sanfilippo Sud)
• Duration: 1 year
• Location: CHU Sainte-Justine, University of Montreal
• Status: Completed
• Start date: May 2022

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