Acronimo: COMBAT

Titolo: COMpetitive Binding and AnTioxidant-based approach to tackle the neuropathology in Mucopolysaccharidoses

Codice Progetto: 2022S9TXMC

Responsabile scientifico per il DMM: Prof. Enrico MORO
Coordinatore: Università degli Studi di PADOVA - Prof. Enrico MORO

Partner-Unità di ricerca: Università degli Studi di Napoli Federico II

Bando: PRIN 2022 - Decreto Direttoriale n. 104 del 02-02-2022
Durata: 28/09/2023 - 27/09/2025 (24 mesi)

Finanziamento progetto: € 220.851,00 - CUP C53D23006520006

 

Abstract del progetto

The design of a breakthrough therapy for the neurological manifestations in Mucopolysaccharidoses should take into account the spectrum of previously described cellular defects triggered by lysosomal dysfunction. These abnormalities range from impaired autophagy and proteostasis with increased oxidative stress, to altered cell signaling transduction, which altogether lead to progressive neuronal cell loss and neuroinflammation. The main goal of this proposal will be the application of a combined drug-based approach to revert some of the brain phenotypic alterations detected in a selected group of Mucopolysaccharidoses (MPSII and MPSIIIB). The two disorders share a common feature, that is the heparan sulfate storage, which is not only associated with lysosomal enlargement, but also with a plethora of concurrent pathological alterations in the extracellular milieu (deregulation of proteoglycans, growth factors and ligands), in the cell membrane (aberrant ligand to receptor interaction), as well as within cells (transcriptomic and proteomic dysregulation, autophagic flux blockade). Therefore, we will address the rescue of these aspects affected by lysosomal enzyme dysfunction by exploiting the combination of selected molecules, which have been preliminarily shown to partially revert some phenotypic abnormalities in each individual Mucopolysaccharidosis. In particular, we will combine the use of delta-tocopherol (Vitamin E) and the natural variant of the hepatocyte growth factor, NK1, to simultaneously target the redox dyshomeostasis and oxidative stress response together with rebalance of the extracellular heparan sulfate levels. To accomplish this goal, we will take advantage of already available experimental models (cultured neurons, Drosophila, zebrafish and mouse models) for the two selected Mucopolysaccharidoses. Each model will be tested with both compounds, either individually or in combination, to recover the neurological abnormalities and prevent the neuroinflammation. The use of non-mammalian animal models for MPSII (Drosophila and zebrafish), already shown to reproduce some phenotypic abnormalities of the human disease, will allow to rapidly address the correct brain targeting of the compounds and verify their ability to rescue the neurological defects from early life stages. On the other hand, the availability of murine models for MPSII and MPSIIIB will enable to strengthen the potentiality of the selected compounds to curtail the neurological defects in a mammalian context. In summary, this proposal intends to establish a valuable combined drug-based approach to correct the neurological phenotype in MPSII and MPSIIIB, in support to the currently developing chimeric enzyme replacement strategy.