Modeling the disease complexity to refine gene/cell therapy treatment strategies

Leukodystrophies (metachromatic leukodystrophy, MLD; globoid cell leukodystrophy, GLD) and GM2 gangliosidosis belong to the wider class of Lysosomal Storage Diseases (LSD), in which deficiency of specific lysosomal enzymes results in storage of undegraded macromolecules in lysosomes, functional impairment and cell death. Many of them display severe involvement of the central nervous system and consequent neurodegeneration. Our previous and current studies aim to study mechanisms of disease pathogenesis and develop novel gene therapy (GT) approaches for these LSD that despite the shared multi-organ pathology display unique features, which may translate in different treatment requirements and/or different outcome of a given treatment. Our long-term goal is to enhance and complement the unique treatment modality provided by GT (i.e. the advantages of enzyme overexpression and widespread biodistribution) to develop innovative and safer therapeutic strategies addressing the specific requirements posed by severe LSD that still lack effective curative options. To this end, a better understanding of the pathogenic events underlying disease onset/progression and of the therapeutic mechanisms of disease correction upon treatments is required. To address this issue we are exploiting several in vivo and in vitro murine and human models, including neural and myeloid cultures, and patient-specific induced pluripotent stem cells (iPSCs), which will offer an unprecedented opportunity to model the disease and to test novel gene transfer strategies.