Intranasal Delivery of pGDNF DNA Nanoparticles Provides Neuroprotection in the Rat 6-Hydroxydopamine Model of Parkinson’s Disease

Abstract

Glial cell line-derived neurotrophic factor (GDNF) gene therapy could offer a disease-modifying treatment for Parkinson's disease (PD). Here, we report that plasmid DNA nanoparticles (NPs) encoding human GDNF administered intranasally to rats induce transgene expression in the brain and protect dopamine neurons in a model of PD. To first test whether intranasal administration could transfect cells in the brain, rats were sacrificed 1 week after intranasal pGDNF NPs or the naked plasmid. GDNF ELISA revealed significant increases in GDNF expression throughout the brain for both treatments. To assess whether expression was sufficient to protect dopamine neurons, naked pGDNF and pGDNF DNA NPs were given intranasally 1 week before a unilateral 6-hydroxydopamine lesion in a rat model of PD. Three to four weeks after the lesion, amphetamine-induced rotational behavior was reduced, and dopaminergic fiber density and cell counts in the lesioned substantia nigra and nerve terminal density in the lesioned striatum were significantly preserved in rats given intranasal pGDNF. The NPs afforded a greater level of neuroprotection than the naked plasmid. These results provide proof-of-principle that intranasal administration of pGDNF DNA NPs can offer a non-invasive, non-viral gene therapy approach for early-stage PD.

Extracellular Vesicles as Nanotherapeutics for Parkinson’s Disease

“…The high concentration of GDNF within the SN protected DAergic neurons and dendritic fibers against the damage induced by 6-OHDA. In addition, the authors observed significant improvements in motor functions [250]. Therefore, these promising findings corroborate the important role played by GDNF to preserve DAergic neurons from cytotoxic triggers.…”

“…Another strategy to increase GDNF levels in the inflamed brain has been developed in 2019 by Aly et al [250]. They induced brain cell transfection in vivo by delivering plasmid DNA (pDNA) encoding GDNF, either alone or mixed with a gelatine solution to form NPs, in a PD rat model.…”

Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

“…As such, VEGF fosters the reorganization of the spinal motor network after SCI [71] and also underlies a protective effect against ischemia [69]. Among currently known neurotrophic factors, GDNF has the most pronounced neuroprotective effect, which is particularly relevant in ischemic brain damage [72,73] and neurodegenerative diseases [74][75][76]. The effects of GDNF on GluR2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reduce the postsynaptic membrane permeability to calcium ions, which may be considered a possible mechanism for protecting neural cells from hypoxic damage [73].…”

Non‐viral nucleic acid delivery to the central nervous system and brain tumors

“…For further exploration, some in vivo studies have been reported. Aly et al . chose to investigate GDNF gene therapy in a rat 6‐hydroxydopamine model of PD.…”

“…For further exploration, some in vivo studies have been reported. Aly et al 30 chose to investigate GDNF gene therapy in a rat 6-hydroxydopamine model of PD. PEGylated poly-L-lysine nanoparticles encapsulating GDNF gene were constructed and delivered to the CNS using a non-invasive route of administration, namely intranasal delivery.…”