title: Brain delivery of microencapsulated GDNF induces functional and structural recovery in parkinsonian monkeys.
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.
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IDISNA), 31008 Pamplona, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Garbayo
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), 31008 Pamplona, Spain; Biochemistry and Genetics Department, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ansorena
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IDISNA), 31008 Pamplona, Spain.
authors.forename: Hugo
authors.initials: H
authors.lastname: Lana
authors.affiliation: Neurology Department, Clínica Universidad de Navarra, 31008 Pamplona, Spain; Neuroscience Division, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: María Del Mar
authors.initials: MD
authors.lastname: Carmona-Abellan
authors.affiliation: Neuroscience Division, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Marcilla
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), 31008 Pamplona, Spain; Neuroscience Division, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Lanciego
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), 31008 Pamplona, Spain; Neurology Department, Clínica Universidad de Navarra, 31008 Pamplona, Spain; Neuroscience Division, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain. Electronic address: rluquin@unav.es.
authors.forename: María Rosario
authors.initials: MR
authors.lastname: Luquin
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IDISNA), 31008 Pamplona, Spain. Electronic address: mjblanco@unav.es.
authors.forename: María José
authors.initials: MJ
authors.lastname: Blanco-Prieto
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002214:Capsules; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D004339:Drug Compounding; D016503:Drug Delivery Systems; D004343:Drug Implants / Q000008:administration & dosage*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000494:pharmacology; D006207:Half-Life; D000882:Haplorhini; D007091:Image Processing, Computer-Assisted; D007267:Injections; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D011699:Putamen; D020127:Recovery of Function; D016896:Treatment Outcome
chemical_list: D002214:Capsules; D004343:Drug Implants; D051100:Glial Cell Line-Derived Neurotrophic Factor
keywords: Drug delivery system; GDNF; Microparticles; Non-human primates; Parkinson's disease