Exploiting novel gene therapy platforms and human-based pre-clinical models to understand biology and advance treatment of genetic neurodegenerative and demyelinating diseases

Leukodystrophies (Metachromatic leukodystrophy, MLD; Globoid cell leukodystrophy, GLD) and GM2 gangliosidoses are lysosomal storage diseases (LSD) in which the lack / reduced activity of lysosomal enzymes causes accumulation of non-degraded macromocolecules with consequent alteration of cellular function. Many LSDs have severe central nervous system involvement and subsequent neurodegeneration. Our studies aim to understand disease mechanisms and to develop new gene therapy approaches for these diseases which, while sharing some pathological traits, have unique characteristics that could justify the need for different approaches, or a different outcome of the same treatment. Our long-term goal is to increase and make more effective current gene therapy strategies for treating LSDs that currently have no therapeutic options. To achieve this goal, we are acting on two main fronts: 1) modifying the lysosomal enzymes in order to make them more bioavailable to affected tissues and cells; 2) modulate neuroinflammation and promote repair of tissue damage. To have a deeper knowledge of the mechanisms underlying the pathology and of the therapeutic correction following treatments, we take advantage of numerous experimental models in vivo and in vitro, including neural stem cells, myeloid cells, and induced pluripotent stem cells obtained from patients (using 2D and 3D models), which represent an ideal system to study pathological mechanisms and to test the efficacy and safety of innovative therapies.