Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain

Lars U Wahlberg; Dwaine F Emerich; Jeffrey H Kordower; William Bell; Tracie Fradet; Giovanna Paolone

doi:10.1016/j.crphar.2020.04.001

Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain

Curr Res Pharmacol Drug Discov. 2020 May 6:1:19-29. doi: 10.1016/j.crphar.2020.04.001. eCollection 2020 Apr.

Authors

Lars U Wahlberg¹, Dwaine F Emerich¹, Jeffrey H Kordower², William Bell¹, Tracie Fradet¹, Giovanna Paolone³

Affiliations

¹ Gloriana Therapeutics Inc., Warren, RI, USA.
² Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
³ Department of Diagnostic and Public Health, Section of Pharmacology, University of Verona P.le, LA Scuro, Verona, Italy.

Abstract

Delivering glial cell line-derived neurotrophic factor (GDNF) to the brain is a potential treatment for Parkinson's Disease (PD). Here we use an implantable encapsulated cell technology that uses modified human clonal ARPE-19 cells to deliver of GDNF to the brain. In vivo studies demonstrated sustained delivery of GDNF to the rat striatum over 6 months. Anatomical benefits and behavioral efficacy were shown in 6-OHDA lesioned rats where nigral dopaminergic neurons were preserved in neuroprotection studies and dopaminergic fibers were restored in neurorecovery studies. When larger, clinical-sized devices were implanted for 3 months into the putamen of Göttingen minipigs, GDNF was widely distributed throughout the putamen and caudate producing a significant upregulation of tyrosine hydroxylase immunohistochemistry. These results are the first to provide clear evidence that implantation of encapsulated GDNF-secreting cells deliver efficacious and biologically relevant amounts of GDNF in a sustained and targeted manner that is scalable to treat the large putamen in patients with Parkinson's disease.

Keywords: Encapsulation; GDNF; Neuroprotection; Neuroregeneration.