Institution: University of Naples Federico II, Naples, Italy
Investigator: Luigi Michele Pavone, Associate Professor of Biochemistry, Department of Molecular Medicine and Medical Biotechnology, Medical School, University of Naples Federico II
Duration: 30 months
Start Date: June 2021
Type of Sanfilippo studied: B
Types of Sanfilippo that could benefit: A, B, C, and D
Research Stage: Translational
Cure Sanfilippo Foundation has funded a research grant to Luigi Michele Pavone, PhD, of University of Naples Federico II (Naples, Italy) to explore a novel therapeutic strategy (heparan sulfate substrate masking) for Sanfilippo syndrome (Mucopolysaccharidoses III, MPS III).
The therapeutic strategy is based on the use of a recombinant protein that is able to reduce glycosaminoglycan (GAG) content and lysosomal defects in fibroblasts (skin cells) from affected patients and to reactivate the cellular signals necessary for the normal growth and development.
Dr. Pavone’s lab previously demonstrated that the recombinant NK1 protein, a natural spliced variant of the hepatocyte growth factor, is able to reduce GAG content and lysosomal defects in primary fibroblasts from MPS patients and to reactivate the FGF signaling by masking the excess of the extra heparan sulfate accumulated outside the cell.
Additionally, Dr. Pavone’s preliminary research shows that this therapy reduces GAGs in the urine and organs and reduces neuroinflammation in the brain of Sanfilippo type B mice; thus, preventing the development of disease symptoms.
The main aim of this next research effort is to test the efficacy of this novel therapy to improve the neurological impairment in both the mouse model of Sanfilippo B and in neuronal cellular models of the disease (generated by Dr. Pavone’s lab).
“The hope is this new therapy could be used alone or in combination with other approaches, and it would likely be applied also to other MPS disorders as the treatment acts upon the heparan sulfate build-up common to most MPS diseases” said Dr. Pavone.
About Substrate-Masking Approach
The following graphic explaining the theory of substrate masking technology is from Dr. Pavone’s previous research.
“Schematic Diagram Depicting the Rationale and the Molecular Mechanism of the Substrate-Masking Technology for the Treatment of MPS Diseases
(Modified from Hacker et al.)
The rationale for the substrate-masking technology is based on the evidence that the equilibrium between HSPGs, morphogens or growth factors, and receptors accounts for the physiological receptor-signaling activation. On the contrary, when HSPG levels on cell membrane are accumulated, signaling receptor activation is diminished due to the increased binding activity of the morphogens or growth factors to the additional GAG chains, thus leading to MPS pathology. A recombinant protein with a high binding affinity for HS and DS saturating the excess of extracellular GAGs may restore the physiological equilibrium between HSPGs, morphogens or growth factors, and receptors and the subsequent signaling.”
Source: De Pasquale V, Sarogni P, Pistorio P, et. al, 2018, “Targeting Heparan Sulfate Proteoglycans
as a Novel Therapeutic Strategy for Mucopolysaccharidoses.” Methods & Clinical Development Vol. 10 September 2018. DOI: https://doi.org/10.1016/j.omtm.2018.05.002
Findings of this work were published February 2023 in Jounrnal of medicinal chemistry, entitled “N-Substituted l-Iminosugars for the Treatment of Sanfilippo Type B Syndrome.” Access the publication.
Picture: Dr. Pavone with members of his team at the University of Naples Federico II in Italy.
This page’s content has been medically reviewed by Dr. Cara O’Neill, FAAP.