MONTREAL, July 15, 2025 - Neurological mucopolysaccharidoses (MPS) are rare genetic lysosomal storage disorders, typically diagnosed in early childhood, that lead to the abnormal cellular accumulation of a complex sugar, heparan sulfate. This buildup disrupts the function of multiple organs, including the central nervous system leading to the most severe forms of the disease, such as MPS type III also known as Sanfilippo Disease or MPS type I known as Hurler disease. Despite recent advances in gene therapy and stem cell therapy, patients affected with the neurological forms of MPS currently lack effective treatments, because lost cognitive functions cannot be restored if treatments are started after appearance of the fist symptoms.
A study led by Prof. Alexey Pshezhetsky, researcher at the Centre de recherche Azrieli du CHU Sainte-Justine, has unraveled a novel pathological mechanism that could pave the way for new therapeutic strategies. The research team discovered that neuraminidase 1 (NEU1)— a well characterized enzyme—shows a secondary deficiency in the brains of individuals with neurological MPS, due to the accumulation of heparan sulfate. NEU1 deficiency, in turn, leads to accumulation of other sugars on the neuronal surface which causes neuronal dysfunction. Notably, this secondary NEU1 deficiency appears to be unique to neurological MPS and is absent in other lysosomal storage disorders, making it a highly promising biomarker for diagnosis and targeted treatment.
The findings, published in the Journal of Clinical Investigation, are the result of over six years of research carried out in collaboration with two CHU Sainte-Justine trainees, TianMeng Xu and Rachel Heon-Roberts, as well as researchers across Europe and the United States. The neuroscience expertise of investigator Bénédicte Amilhon, also a researcher at CHU Sainte-Justine, was instrumental in understanding the functional impact of NEU1 deficiency on neurons.
Promising laboratory results
By analyzing brain tissue from MPS patients and using mouse models of the disease, the team found that heparan sulfate accumulation leads to a marked reduction of NEU1 in the brain. “Initially, the finding of NEU1 deficiency was completely unexpected,” explains Prof. Pshezhetsky. “In MPS research, it is generally accepted that all lysosomal enzymes except for those with the primary genetic defects are overexpressed. But this was not the case for NEU1—which prompted us to investigate further.”
The results are promising, since overexpressing NEU1 in cortical neurons derived from MPS III patient-induced pluripotent stem cells (iPSCs) restored the levels of key synaptic markers. Furthermore, stereotaxic injection of a lentivirus overexpressing NEU1 into the hippocampus and cerebral cortex of MPS III mice not only restored these markers but also improved cognitive functions such as short-term memory and anxiety.
Toward a New Therapeutic Target?
“To our knowledge, this is the first study to link NEU1 deficiency to heparan sulfate accumulation in neurological MPS,” notes Prof. Pshezhetsky, who is also a professor at the Université de Montréal. Building on this discovery, the researcher and his team now aim to investigate this novel complementary therapeutic strategy: while gene editing therapies halt the progression of the disease, targeting NEU1 could potentially help restore lost neuronal function in patients already showing symptoms of MPS.