Gene/neural stem cell therapy for lysosomal storage diseases
Leukodystrophies 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. These are rare genetic “global” diseases affecting the nervous system and peripheral organs. Results from basic science, pre-clinical studies using relevant disease animal models (including our studies) and clinical interventions have established the therapeutic potential of gene/cell therapy for the treatment of these diseases as it has the potential to provide a permanent source of the deficient enzyme. However, the failure of every approach tested so far in providing a definitive treatment to CNS damage and neurologic symptoms indicates that i) innovative combined strategies should be developed to target all the affected organs/tissues in an appropriate time-window of opportunity; ii) a deeper knowledge of CNS pathophysiology is needed to understand obstacles that need to be overcome for the implementation of these therapies. Our research activity is focused on testing the safety and efficacy of innovative combined gene/cell therapies (using intracerebral gene delivery as well as neural and hematopoietic stem cells). In parallel, we are interested the evaluation of the early pathogenic events occurring in the disease murine models due to the genetic enzymatic deficiency, trying to understand the possible impact of these events on the therapeutic outcome. To address this issue we are exploiting several in vitro experimental setting, including neural stem cell cultures as well as patient-specific induced pluripotent stem cells (iPSCs), which will offer an unprecedented opportunity to model the disease and to test novel gene transfer strategies.