TARGETING LYSOSOMAL FAILURE IN NEURODEGENERATIVE DISEASE: ENZYME RESTORATION STRATEGIES BASED ON A NANOERT PLATFORM FOR PARKINSON’S AND RELATED DISORDERS

Lysosomal dysfunction is rising as a key central pathogenic mechanism in neurodegenerative disorders, particularly Parkinson’s disease (PD), and in rare lysosomal storage disorders with neurological involvement. Impaired activity of lysosomal enzymes leads to defective substrate clearance, disrupted proteostasis, and accumulation of neurotoxic species. However, effective therapeutic strategies aimed at restoring lysosomal enzyme function in the nervous system remain limited.
Here, we present the development of a nano–enzyme replacement therapy (nanoERT) platform designed to enhance the stability, intracellular trafficking and delivery of recombinant lysosomal enzymes. This platform enables sustained lysosomal enzymatic activity in disease-relevant cellular and in vivo models.
Our lead compound, nanoGBA, is based on glucocerebrosidase (GBA), a lysosomal enzyme whose deficiency causes Gaucher disease and represents the strongest genetic risk factor for PD. NanoGBA efficiently delivers active GBA to lysosomes, restores glucocerebrosidase activity, and significantly reduces sphingolipid accumulation both in vitro and in vivo. These results demonstrate effective correction of lysosomal dysfunction associated with neurodegeneration.
Beyond GBA, we have extended this technology to other valuable lysosomal enzymes in the context of neurodegenerative processes. In particular, we have successfully generated nanoCTSD, based on cathepsin D, a key protease involved in α-synuclein degradation and neuronal homeostasis. Additional lysosomal enzymes linked to rare diseases with neurological manifestations are currently under evaluation.
Overall, our findings support nanoERT as a versatile therapeutic strategy to restore lysosomal function, opening new avenues for the treatment of Parkinson’s disease and other neurodegenerative and rare neurological disorders driven by lysosomal failure.