Combination of stem cell transplantation and cathepsin B inhibitors for treatment of Sanfilippo

March 27, 2024

Chief investigator Alexey Pshezhetsky, PhD, of Centre Hospitalier Universitaire Sainte-Justine, Universite de Montreal

Cure Sanfilippo Foundation and Sanfilippo Children’s Foundation (Australia) have awarded a Translational Grant to Professor Alexey Pshezhetsky at the Centre Hospitalier Universitaire Sainte-Justine, University of Montreal.

Professor Pshezhetsky and his team will investigate if an amyloid-blocking therapy combined with bone marrow transplantation can prevent the development of progressive brain disease in mice with Sanfilippo types A, B and C.

Grant Details

Project title: Combination of HSCP transplantation and cathepsin B inhibitors for treatment of Sanfilippo disease

Chief investigator: Professor Alexey Pshezhetsky

Duration: 2 years

Location: Centre Hospitalier Universitaire Sainte-Justine, Universite de Montreal

Start date: April 2024

Grant Description

Professor Pshezhetsky and the team have identified a new mechanism that may contribute to neurodegeneration in Sanfilippo. They found that a lysosomal enzyme, cathepsin B, can cause the build-up of toxic amyloid materials in the brain of a Sanfilippo type C mouse model. The amyloid materials are similar to those seen in the brains of people with Alzheimer’s disease.

Using the drug E64, which blocks cathepsin B, the team was able to significantly reduce amyloid materials in the brain of the Sanfilippo type C mouse model. The treatment also resulted in reduced cell death of neurons and improvements in behavioral symptoms. However, there was no reduction in brain inflammation, which is thought to also contribute to disease symptoms in Sanfilippo. Therefore, in this project, Professor Pshezhetsky and his team propose to combine E64 treatment with bone marrow transplantation, which can reduce inflammation.

First, they will determine the dose and regimen of E64 treatment that produces the best outcome in a mouse model of Sanfilippo type C. The team will also test E64 in Sanfilippo types A and B mouse models to see if the drug can improve behavioral symptoms, stop amyloid build-up, and reduce the death of neurons as previously seen in the type C mouse model.

Then, the team will test the combined E64 therapy and bone marrow transplantation in Sanfilippo types A, B and C mouse models and its ability to improve behavior and memory. This should confirm whether the combined therapy shows promise for patients with Sanfilippo.

As both therapies are used in the clinic or approved for clinical trials for other conditions, the results have the potential to provide a relatively swift impact for patients living with Sanfilippo who currently have no treatment options.

“Along with our colleagues at SCF in Australia, Cure Sanfilippo Foundation is pleased to co-fund this important translational work being conducted in Prof. Pshezhetsky’s lab. Results from this study aim to advance our understanding of transplant outcomes and amyloid accumulation in Sanfilippo mouse models while generating proof of concept for potential future studies in patients,” said Dr. Cara O’Neill, Chief Science Officer at Cure Sanfilippo Foundation.

“This project may provide additional evidence to support cathepsin B as a therapy target for Sanfilippo,” said Dr Lisa Melton, Head of Research at Sanfilippo Children’s Foundation. “As cathepsin B is already a therapy target for Alzheimer’s and other neurodegenerative diseases, results from these fields may also benefit people with Sanfilippo.”

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

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