We mainly focus our research interests on Mucopolysaccharidoses (MPSs), a cluster of Lysosomal Storage Disorders, due to the deficit of the enzymes normally catabolizing mucopolysaccharides (or glycosaminoglycans) inside the lysosomal compartment. Being lysosomal enzymes coded by housekeeping genes, MPSs generally affect most, if not all, organ-systems, including the brain in more than 70% of the cases. Although still incurable, in the last 10-15 years some MPSs have taken advantage of the availability of the Enzyme Replacement Therapy (ERT), consisting of weekly administrations of the functional enzyme. The treatment though has shown so far some peripheral efficacy, but unfortunately does not help the CNS disease, due to the inability of the enzymes to cross the blood-brain barrier. In addition, brain pathogenesis remains quite obscure for these diseases, while the understanding of its origin and progression would be extremely helpful to both monitor patients prognosis and detect new potential therapeutic targets. Main objectives of the research team are therefore the comprehension of the brain pathogenesis in these disorders and relative possible treatments, by using different in vitro and in vivo models.

Projects of the research group

– In the last decade, the Laboratory has been largely involved in the evaluation and application, in vitro and in vivo, of a nanoparticle-based approach, functionalized to obtain drug brain-targeting, as a potential non-invasive therapeutic approach for MPS brain disease. We have successfully delivered Albumin, as a model high MW molecule, to the brain of MPS I and MPS II mouse models (Salvalaio et al. PLoS One 2016 May 26;11(5):e0156452). We have also successfully delivered the recombinant form of the enzyme iduronate 2-sulfatase to the brain of the MPS II mouse model (Rigon et al. Int J Mol Sci 2019 Apr 24; 20(8):2014). We have recently optimized the NPs-mediated strategy, by increasing the enzyme stability and its encapsulated amount, though maintaining efficiency and efficacy, as shown by the in vitro results obtained (unpublished), while the in vivo delivery is ongoing.

– With the aim of understanding the onset of brain pathogenesis in these disorders and also its progression, we are characterizing the brain parenchyma of the MPS II mouse model by evaluating different biomarkers at several progressive age of the animal, which will be also useful to monitor therapeutic efficacy of brain-targeted approaches at different animal ages. We are at the moment completing the analysis performed so far by evaluating the very early stages of life.

– In the last couple of years we have started a new project in collaboration with the Dept. of Pharmaceutical and Pharmacological Sciences, University of Padova, aiming at generating and characterizing Drosophila models of mucopolysaccharidoses. Our PhD student has generated a Drosophila knock-down model of MPS I, whose characterization is almost
complete, showing that the fly may represent a good model of the disease. Drosophila is a fast and valuable model to study pathogenesis issues and also a good tool for screening of therapeutic molecules.

– Our interest in the MPS brain pathogenesis is also focused on the identification of the potentially altered pathways resulting in the severe forms of MPS, leading to neuro-cognitive and behavioral impairment. This project is conducted by generating induced pluripotent stem cells (IPSC) starting from human primary fibroblasts.

– Within the issue of Advanced Diagnostics, we have recently set-up and validated a targeted panel for the contemporary molecular analysis of 50 Lysosomal Storage Disorders (Zanetti et al. J Mol Diagn 2020 Apr; 22(4): 488-502). We have also completed the “mutation update” of the ARSB gene, through a re-classification of all published variants, according to ACMG (American College of Medical Genetics and Genomics) (Tomanin et al. Hum Mutat 2018 Dec;39(12):1788-1802); in the last few months, this analysis, helping to perform a correct molecular diagnosis, has been extended to other 2 genes of interest, one of which is under completion.

Diagnostic activity: the laboratory also performs some biochemical and molecular analyses related to the diagnosis of Mucopolysaccharidoses