Abstract:Parkinson's disease (PD) is a progressive neurodegenerative disorder that results from the loss of the A9 nigrostriatal dopamine neurons. The current therapies available for treating PD provide symptomatic relief by replacing or mimicking dopamine in the brain, but do not actually prevent or reverse the loss of these dopaminergic neurons. Glial cell--line derived neurotrophic factor (GDNF) has disease--modifying potential in PD due to its ability to promote the survival of dopamine neurons both in vitro and in vivo. GDNF has been shown to be neuroprotective in several animal models of PD. However, its clinical potential has been limited thus far by its inability to cross the blood--brain barrier (BBB) and the need for invasive intracranial delivery. The main objective of this thesis was to develop an approach to non--invasively deliver a continuous source of GDNF to the brain at levels that are neuroprotective inParkinson's Disease, whilst minimizing systemic exposure. To do so, this project investigated the intranasal delivery of non--viral hGDNF expression plasmids (pGDNF_1b and pUGG) compacted into nanoparticles (NPs). Intranasal delivery allows large therapeutics to circumvent the BBB while avoiding peripheral exposure, while a gene therapy approach would provide a long--term renewable source of GDNF in the brain regions associated with PD. These NPs, developed by Copernicus Therapeutics, Inc., are composed of 10 kDa polyethylene glycol--substituted lysine 30--mers (CK30PEG10k) which unimolecularly compact the plasmid DNA into neutrally charged NPs.The first goal of this project was to determine if intranasal administration of pGDNF_1b DNA NPs produces a neuroprotective and neurotrophic effect on rat substantia nigra (SN)
Glial cell line‐derived neurotrophic factor (GDNF) has been shown to be neuroprotective toward substantia nigra (SN) dopamine neurons in animal models of Parkinson's disease (PD) and in some clinical trials. However, its delivery to brain has required invasive surgical routes that are untenable for many patients with PD. The goal of these experiments was to test whether intranasal delivery of a GDNF expression plasmid could protect dopamine cells in the rat 6‐hydroxydopamine (6‐OHDA) model of PD. If successful, intranasal delivery of pGDNF could provide a renewable source of GDNF within the brain without need for surgical injections or frequent re‐dosing.Rats were given intranasal saline, naked pGDNF or pGDNF in a PEGylated polylysine nanoparticle (NP) preparation 7 days prior to receiving a unilateral 6‐OHDA lesion. Three weeks after 6‐ OHDA, rotational behavior to 5 mg/kg d‐amphetamine was assessed, followed by sacrifice. Tyrosine hydroxylase (TH) immunohistochemistry revealed a significant reduction in lesion severity in the SN of rats given intranasal pGDNF NPs versus those given naked pGDNF or saline. In addition, rotational behavior was reduced in rats treated with pGDNF NPs. These results demonstrate the utility of intranasal delivery of pGDNF NPs as a non‐invasive means of gene therapy for PD and possibly other diseases of the brain. Support provided by: 2011–12 Northeastern University Tier 1 Seed Grant and the M.J. Fox Foundation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.