Globoid Cell Leukodystrophy (GLD) is a neurodegenerative lysosomal storage disease (LSD) due to the genetic deficiency of beta-galactosylceramidase (GALC). The rapid disease progression of the infantile forms and the severe neurodegeneration pose major issues for the development of effective treatments. Currently, GLD patients lack real therapeutic options.

The promising but still modest results obtained in pre-clinical models using innovative approaches (i.e. gene/cell therapies) highlight the difficulty of providing timely (before onset of symptoms), pervasive (to all affected tissues), and long-term (ideally for the whole life) therapeutically relevant levels of GALC enzyme in a safe manner. This difficulty relies in part on our imperfect understanding of the mechanisms of enzymatic correction in the different cell types that are targets (i.e brain cells) or effectors (the progeny of blood stem cells) in the context of gene/cell therapy approaches. This is a gap that we aim to fill with this study.

The long-term goal of this study is to design therapeutic approaches based on solid mechanistic ground achieved using relevant GLD models. We hypothesise that the use of a GALC enzyme engineered to increase its secretion and capability to cross the blood-brain barrier may boost the efficacy of gene/cell therapy approaches in GLD, as it does in pre-clinical models of similar diseases. Taking advantage of our expertise in the study and treatment of GLD, and building upon the availability of novel reagents and tools, we will design chimeric GALC enzymes that will be tested for secretion/bioavailablity, safety, and modality of action in direct comparison with the unmodified enzyme in relevant cells types (i.e. hematopoietic stem/progenitor cells and differentiated progeny) and, ultimately, in GLD mice.

Successful completion of this project will increase mechanistic knowledge of disease correction in GLD, paving the way to novel gene/cell therapy strategies using modified enzymes to be applied as independent treatments and/or in combination to achieve global disease correction.

Project financed by ELA up to: 95 000 €