Montréal, May 27, 2024 – For the very first time, a team co-headed by CHU Sainte-Justine researcher Alexey Pshezhetsky succeeded in resolving the unique structure of the HGSNAT, the enzyme which deficiency causes the Sanfilippo syndrome, a rare pediatric disease that affects the central nervous system. Through a collaboration with a team from Shanghai University the structure of this enzyme and the mechanism of its function was revealed using high-performance cryogenic-electron microscopy. This discovery will allow to develop new treatments for Sanfilippo disease as well as for similar fatal neurodegenerative disorders. 

A deadly and complex disease 

Sanfilippo syndrome is a metabolic condition resulting from genetic mutations that cause the accumulation of a molecule called heparan sulfate in the brain cells. The HGSNAT enzyme is essential for degradation of heparan sulfate. In Sanfilippo syndrome genetic mutations in HGSNAT do not allow it to fold and function correctly. As a result, heparan sulfate accumulates causing neuronal death and leading to dementia in the affected children. “In basic terms, Sanfilippo is similar to the Alzheimer’s disease, but it occurs in a child of two or three years old,” explained researcher Alexey Pshezhetsky, who is also a professor at Université de Montréal. “Starting from this age, the affected children stagnate in their development and then regress, dying toward the end of adolescence.”

Although there is currently no treatment for this pathology, a lot of hope is invested in what is called “chaperone therapy” (CT). CT consists of administering a small molecule that binds with the mutant enzyme and helps it fold properly, so it can function normally. To determine which molecule is best suited to binding with the enzyme, a reliable model of its structure is required – which the team has succeeded in developing using cryogenic-electron microscopy.

Paving the way to new treatments  

Being an Elisa Linton Research Chair in Lysosomal Diseases, professor Alexey Pshezhetsky is actively working on transfering this new knowledge to clinics. “Together with the University of Alberta professor Christopher Cairo, we are currently determining which small molecules bind best to the enzyme and, therefore, would be the most effective to treat the disease,” he added.

Discussions are already underway with other Canadian researchers to study treatments that combine CT with gene therapy or stem cell-based therapy. “A confidence in the effectiveness of such combined approaches is currently growing, and we are certain that over the next few years a new therapeutic strategy will be developed to the benefit of affected children and their families,” he concluded.