MUCOPOLYSACCHARIDOSIS TYPE IIIB: FROM PATHOGENESIS TO THERAPY

Mucopolysaccharidosis type IIIB (MPS IIIB) is a genetic disease caused by the deficiency of alpha-N-acetylglucosaminidase (NAGLU), an enzyme involved in degradation of the mucopolysaccharide heparan sulfate, a macromolecule found in the extracellular environment. This deficiency results in the accumulation of partially degraded molecules in the cells of affected patients and this, in turns, by unclear reasons, leads to the clinical manifestations. Affected patients are, in fact, characterized by organs alterations associated to aggressive behaviour and, as main clinical sign, mental retardation resulting from a severe central nervous system impairment. So far, the bases of this neuronal impairment, i.e. the pathogenesis of the disease, are not well understood, nor efficient therapies are available. The proposed project aims to use the available MPS IIIB murine model both for pathogenesis and therapeutic studies. For the first item, the project will get a better knowledge of the molecular bases of the disease by analysing the differences in gene expression in tissues from the central nervous system of affected mice compared to normal controls, and by studying the intracellular effects of these alterations. For the therapeutic studies, the project aims to evaluate the ability of intracranial injections of viral particles modified to be safe and to provide the lacking enzyme, to correct the brain pathology.