GDNF revisited: A novel mammalian cell-derived variant form of GDNF increases dopamine turnover and improves brain biodistribution

Richard Grondin, O. Meagan Littrell, Zhiming Zhang, Yi Ai, Peter Huettl, Francois Pomerleau, Jorge E. Quintero, Anders H. Andersen, Mallory J. Stenslik, Luke H. Bradley, Jack Lemmon, Michael J. O'Neill, Don M. Gash, Greg A. Gerhardt

Research output: Contribution to journalReview articlepeer-review

24 Scopus citations

Abstract

Parkinson's disease (PD) is a disorder affecting dopamine neurons for which there is no cure. Glial cell line-derived neurotrophic factor (GDNF) and the closely related protein neurturin are two trophic factors with demonstrated neuroprotective and neurorestorative properties on dopamine neurons in multiple animal species. However, GDNF and neurturin Phase-2 clinical trials have failed to demonstrate a significant level of improvement over placebo controls. Insufficient drug distribution in the brain parenchyma has been proposed as a major contributing factor for the lack of clinical efficacy in the Phase-2 trial patients. To address this issue, a novel mammalian cell-derived variant form of GDNF (GDNFv) was designed to promote better tissue distribution by reducing its heparin binding to the extracellular matrix and key amino acids were substituted to enhance its chemical stability. Administration of this fully glycosylated GDNFv in the normal rat striatum increased dopamine turnover and produced significantly greater brain distribution than E. coli-produced wildtype GDNF (GDNFwt). Intrastriatal GDNFv also protected midbrain dopamine neuron function in 6-hydroxydopamine-lesioned rats. Studies conducted in normal adult rhesus macaques support that GDNFv was well tolerated in all animals and demonstrated a greater volume of distribution than GDNFwt in the brain following intrastriatal infusion. Importantly, favorable physiological activity of potential therapeutic value was maintained in this variant trophic factor with significant target activation in GDNFv recipients as indicated by dopamine turnover modulation. These data suggest that GDNFv may be a promising drug candidate for the treatment of PD. Additional studies are needed in non-human primates with dopamine depletion. This article is part of the Special Issue entitled ‘Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders’.

Original languageEnglish
Pages (from-to)28-36
Number of pages9
JournalNeuropharmacology
Volume147
DOIs
StatePublished - Mar 15 2019

Bibliographical note

Funding Information:
The authors would like to thank Peter Hardy for MRI acquisition as well as April Butler, Eric Forman, Arthur Lemons, Taylor Lundeen, David A. Price and Ryan Weeks for their excellent technical assistance with GDNF(wt/v) administration in non-human primates conducted at the University of Kentucky. We would also like to thank the following individuals for scientific advice and assistance with the GDNF(wt/v) studies in non-human primates: Mahmood Ghanem, Linda O'Bryan, John R. Sims, Rosamund C. Smith, Mark Thomas, Bernice Ellis, Pamela Mitchell and Victor Wroblewski who were employees of Eli Lilly & Co. at the time the work was completed as well as David Stiles, Keith Hieldebrand, Brenda K. Schultz, and Lisa L. Shafer who were employees of Medtronic Inc. at the time the work was completed. GDNF(wt/v) studies in non-human primates were supported by Eli Lilly&Co. (Indianapolis, IN) and Medtronic. (Minneapolis, MN).

Funding Information:
The authors would like to thank Peter Hardy for MRI acquisition as well as April Butler, Eric Forman, Arthur Lemons, Taylor Lundeen, David A. Price and Ryan Weeks for their excellent technical assistance with GDNF(wt/v) administration in non-human primates conducted at the University of Kentucky. We would also like to thank the following individuals for scientific advice and assistance with the GDNF(wt/v) studies in non-human primates: Mahmood Ghanem, Linda O'Bryan, John R. Sims, Rosamund C. Smith, Mark Thomas, Bernice Ellis, Pamela Mitchell and Victor Wroblewski who were employees of Eli Lilly & Co. at the time the work was completed as well as David Stiles, Keith Hieldebrand, Brenda K. Schultz, and Lisa L. Shafer who were employees of Medtronic Inc. at the time the work was completed. GDNF(wt/v) studies in non-human primates were supported by Eli Lilly&Co . (Indianapolis, IN) and Medtronic . (Minneapolis, MN).

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

  • GDNF variant
  • Neurotrophic factors
  • Neurturin
  • Parkinson's disease

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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