Brain delivery of microencapsulated GDNF induces functional and structural recovery in parkinsonian monkeys

• Published in: Biomaterials 2016-12, Vol.110, p.11-23
• Main Authors: Garbayo, Elisa, Ansorena, Eduardo, Lana, Hugo, Carmona-Abellan, María del Mar, Marcilla, Irene, Lanciego, José Luis, Luquin, María Rosario, Blanco-Prieto, María José
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Brain; Brain - drug effects; Brain - pathology; Brain - physiopathology; Capsules; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Degeneration; Dentistry; Disease Models, Animal; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - pathology; Dopaminergic Neurons - physiology; Drug Compounding; Drug delivery system; Drug Delivery Systems; Drug Implants - administration & dosage; Effectiveness; GDNF; Glial Cell Line-Derived Neurotrophic Factor - administration & dosage; Glial Cell Line-Derived Neurotrophic Factor - pharmacology; Half-Life; Haplorhini; Image Processing, Computer-Assisted; Injections; Mathematical models; Microparticles; Monkeys; Neurons; Non-human primates; Parkinson's disease; Parkinsonian Disorders - drug therapy; Proteins; Putamen; Recovery of Function; Safety; Treatment Outcome
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2016.09.015

Abstract Glial cell line-derived neurotrophic factor (GDNF) remains the most potent neurotrophic factor for dopamine neurons. Despite its potential as treatment for Parkinson's disease (PD), its clinical application has been hampered by safety and efficacy concerns associated with GDNF's short in vivo half-life and with significant brain delivery obstacles. Drug formulation systems such as microparticles (MPs) may overcome these issues providing protein protection from degradation and sustained drug release over time. We therefore sought to evaluate the efficacy and safety of GDNF delivered via injectable biodegradable MPs in a clinically relevant model of PD and to investigate the mechanism contributing to their beneficial effects. MPs were injected unilaterally into the putamen of parkinsonian monkeys with severe nigrostriatal degeneration. Notably, a single administration of the microencapsulated neurotrophic factor achieved sustained GDNF levels in the brain, providing motor improvement and dopaminergic function restoration. This was reflected by a bilateral increase in the density of striatal dopaminergic neurons 9 months after treatment. Moreover, GDNF was retrogradely transported to the substantia nigra increasing bilaterally the number of dopaminergic and total neurons, regardless of the severe degeneration. GDNF-MP injection within the putamen elicited no adverse effects such as immunogenicity, cerebellar degeneration or weight loss. MPs are therefore a safe, efficient vehicle for sustained protein delivery to the brain, supporting the therapeutic benefit of GDNF when encapsulated within MPs for brain repair. Overall, these findings constitute important groundwork for GDNF-MP clinical development.