Effective GDNF brain delivery using microspheres—A promising strategy for Parkinson's disease

Abstract

Glial cell line-derived neurotrophic factor (GDNF) has shown promise in the treatment of neurodegenerative disorders of basal ganglia origin such us Parkinson's disease (PD). In this study, we investigated the neurorestorative effect of controlled GDNF delivery using biodegradable microspheres in an animal model with partial dopaminergic lesion. Microspheres were loaded with N-glycosylated recombinant GDNF and prepared using the Total Recirculation One-Machine System (TROMS). GDNF-loaded microparticles were unilaterally injected into the rat striatum by stereotaxic surgery two weeks after a unilateral partial 6-OHDA nigrostriatal lesion. Animals were tested for amphetamineinduced rotational asymmetry at different times and were sacrificed two months after microsphere implantation for immunohistochemical analysis. The putative presence of serum IgG antibodies against rat glycosylated GDNF was analyzed for addressing safety issues. The results demonstrated that GDNF-loaded microspheres, improved the rotational behavior induced by amphetamine of the GDNF-treated animals together with an increase in the density of TH positive fibers at the striatal level. The developed GDNF-loaded microparticles proved to be suitable to release biologically active GDNF over up to 5 weeks in vivo. Furthermore, none of the animals developed antibodies against GDNF demonstrating the safety of glycosylated GDNF use.

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems

“…Equally, it is generally accepted that successful translation of GDNF to clinical practice will first require resolving the crucial delivery issues posed by NF. Different strategies including direct gene transfer using recombinant virus (For review see [12]) and polymeric MP has been proposed to improve protein delivery to the brain [11,36]. All research using GDNF-PLGA-MP in rat PD models reported animal functional recovery together with increase in striatal DArgic innervation [36,37].…”

“…Different strategies including direct gene transfer using recombinant virus (For review see [12]) and polymeric MP has been proposed to improve protein delivery to the brain [11,36]. All research using GDNF-PLGA-MP in rat PD models reported animal functional recovery together with increase in striatal DArgic innervation [36,37]. In the next step, our recent studies evaluating GDNF-MP efficacy in a primate PD model demonstrated that long-term controlled brain delivery of microencapsulated GDNF induced functional and structural recovery of the dopaminergic nigrostriatal pathway (Unpublished results).…”

Increased antiparkinson efficacy of the combined administration of VEGF- and GDNF-loaded nanospheres in a partial lesion model of Parkinson’s disease

“…27 In particular, the efficacy of NTFs such as GDNF, or angiogenic factors like VEGF, in the upregulation of essential neurogenic processes makes them ideal candidates for modifying the evolution of this disorder. 4,5,28 Previous studies published by our group, as well as research conducted by numerous other laboratories, 16,29,30 has demonstrated that the administration of VEGF or GDNF improves behavioral deficits as well as decreases neuronal degeneration in different animal models of neurodegenerative disorders. 7,11,20 Nevertheless, the essential problems for the application of these hydrophilic molecules are their short half-life and rapid degradation rate in vivo.…”

Brain Drug Delivery Systems for Neurodegenerative Disorders

“…The failure brought some doubt about trophic factor delivery for PD treatment. Different strategies including direct gene transfer using recombinant adeno-associated virus and PLGA microparticles were proposed to improve brain GDNF delivery [39][40][41][42][43][44].…”

“…All the studies using GDNF-PLGA microspheres reported an animal functional recovery together with an increase in dopaminergic innervation in the striatum due to the sprouting of the fibers spared by the lesion. Moreover, none of the animals that received the glycosylated protein developed antibodies against GDNF demonstrating the safety of glycosylated GDNF use [41].…”