Diagnosis and Therapy of Lysosomal Disorders

Research Activity

The Laboratory focuses its research on Mucopolysaccharidoses (MPSs), a cluster of 12 Lysosomal Storage Disorders, due to the deficit of the enzymes catabolizing mucopolysaccharides (GAG) inside lysosomes, thus causing their severe accumulation within lysosomes and in the extracellular matrix. MPSs generally affect most organ-systems, including CNS, in more than 70% of the cases.
For many years, only symptomatic therapies were available for MPSs, while haematopoietic stem cell transplantation has been so far successfully applied only to MPS I, since its application to other MPSs has shown controversial results. More recently, some MPSs benefit from Enzyme Replacement Therapy (ERT), the weekly administration of the functional enzyme. ERT shows some peripheral efficacy, but is mostly ineffective on the CNS disease, since enzymes cannot cross the BBB. Furthermore, brain pathogenesis remains quite obscure, while its understanding would be extremely helpful to monitor patients’ prognosis and detect new therapeutic targets.
Important objectives of our research are therefore the comprehension of MPS brain pathology and its possible treatment, by using in vitro and in vivo models.
We also conduct research activity on the clinical side, with the follow-up of MPS patients under ERT, to monitor disease progression and treatment efficacy. Moreover, in the last 6 years we conducted three projects of Mutation Update on the genes ARSB, GALNS and IDS, causing MPS VI, MPS IVA and MPS II respectively, performing a complete molecular classification of all variants described for the 3 genes.
In the last decade the laboratory has published 30 peer-reviewed articles, 1 manuscript is at the moment under revision and 3 in preparation.

Projects of the research group

The comprehension of the brain pathogenesis and its progression in MPS II has been completed in the mouse model for the disease (manuscript in preparation), while it is still under analysis in the Drosophila model. These in vivo studies should help to elucidate the onset of the neurological impairment during the disease progression and the molecular alterations implicated.
We focused on the identification of the potentially altered pathways resulting in the severe neuronopathic forms of MPS. To this aim we used in vitro human neural models. We generated induced pluripotent stem cells starting from human primary fibroblasts [Casamassa et al 2022, PMID:35759972]. Moreover, in collaboration with the Dept. of Molecular Medicine, UNIPD, a second in vitro model was generated, an IDS knockout human neuronal cell line [Badenetti et al 2023, PMID:37357221]. Preliminary findings allow to hypothesize that neuronal differentiation might be significantly affected by IDS functional impairment.
In the last years, we started a collaboration with the Dept. of Pharmaceutical and Pharmacological Sciences, UNIPD, aiming at generating/characterizing Drosophila models of mucopolysaccharidoses. A Drosophila knock-down model of MPS I, showed to be a good model of the disease [De Filippis et al 2021, PMID:35011691]. An MPS II fly model, generated in collaboration with the LIMES Institute in Bonn (Germany), was used to test the antioxidant efficacy of Vitamin E and the improvement of the lysosomal/mitochondrial impairment [Rigon et al, unpublished].
We conducted an international study which has completed the “mutation update” of the GALNS gene (whose mutations cause MPS IVA), through a re-classification of all published variants and the description of 68 novel ones [Zanetti et al 2021, PMID:34387910]. In the last two years, this analysis has been extended to the gene IDS (whose variants cause MPS II) [Zanetti, D’Avanzo and Tomanin, submitted].
A search of molecular biomarkers allowing a faster diagnostic procedure and a monitoring of ERT efficacy was performed by analyzing urine samples obtained from suspected MPS patients [D’Avanzo et al 2023, PMID:36979466], and from IDS knock-out mice under ERT (Maccari et al 2022, PMID:35816218). Both investigations conducted through a Mass Spectrometry analysis.
In the last 3 years we published 3 reviews: on MPS VI [D’Avanzo et al 2021, PMID:34948256], on the treatment of Neurometabolic Diseases [Begley et al 2024, PMID:38963225] and on the brain-targeting therapeutic approaches in MPS II [Zanetti and Tomanin, 2024, PMID:39177874].
The Laboratory also performed biochemical and molecular analyses related to MPS diagnosis, and follow-up of MPS patients under ERT.