Gene therapy device-based delivery of progranulin, prosaposin, and GDNF as a combined precision and neurorestorative therapy in the rat 6-OHDA model of parkinsonism

Abstract

: Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disorder, characterized by a progressive degeneration of dopaminergic neurons, leading to significant motor impairments frequently associated with cognitive dysfunction and comorbidities in the elderly. Current treatments of PD are primarily symptomatic, highlighting the urgent need for disease-modifying therapies. An increasing body of evidence supports the pivotal role of lysosomal dysfunction in PD pathogenesis, providing new targets for therapeutic approaches. Particularly, recent studies suggest that among the genes implicated in PD are GRN and PSAP, encoding for progranulin (PGRN) and prosaposin (PSAP), respectively. We proved that conditioned media from a Gene Therapy Device-based delivery system (GTD)-PGRN, -PSAP, and -PGRN+PSAP were internalized by primary cortical neurons, leading to enhanced glucocerebrosidase (GCase) activity. Furthermore, we developed a GTD-delivered therapy to target lysosomal dysfunction and support the dopaminergic system, combining the lysosomal factors PGRN and PSAP with the neurorestorative glial cell line-derived neurotrophic factor (GDNF). Interestingly, each factor provided neuroprotection to dopaminergic neurons and preserved motor function in a 6-hydroxydopamine (6-OHDA)-induced neurotoxicity model. Furthermore, eight-month treatments with GTD-PSAP and PSAP+GDNF resulted in significant neurorecovery effects on dopaminergic neurons and motor deficits following 6-OHDA injection