GDNF-expressing macrophages restore motor functions at a severe late-stage, and produce long-term neuroprotective effects at an early-stage of Parkinson's disease in transgenic Parkin Q311X(A) mice

Yuling Zhao, Matthew J. Haney, Yeon S. Jin, Olga Uvarov, Natasha Vinod, Yueh Z. Lee, Benjamin Langworthy, Jason P. Fine, Myosotys Rodriguez, Nazira El-Hage, Alexander V. Kabanov, Elena V. Batrakova

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

There is an unmet medical need in the area of Parkinson's disease (PD) to develop novel therapeutic approaches that can stop and reverse the underlying mechanisms responsible for the neuronal death. We previously demonstrated that systemically administered autologous macrophages transfected ex vivo to produce glial cell line-derived neurotrophic factor (GDNF) readily migrate to the mouse brain with acute toxin-induced neuroinflammation and ameliorate neurodegeneration in PD mouse models. We hypothesized that the high level of cytokines due to inflammatory process attracted GDNF-expressing macrophages and ensured targeted drug delivery to the PD brain. Herein, we validated a therapeutic potential of GDNF-transfected macrophages in a transgenic Parkin Q311X(A) mice with slow progression and mild brain inflammation. Systemic administration of GDNF-macrophages at a severe late stage of the disease leaded to a near complete restoration of motor functions in Parkin Q311X(A) mice and improved brain tissue integrity with healthy neuronal morphology. Furthermore, intravenous injections of GDNF-macrophages at an early stage of disease resulted in potent sustained therapeutic effects in PD mice for more than a year after the treatment. Importantly, multiple lines of evidence for therapeutic efficacy were observed including: diminished neuroinflammation and α-synuclein aggregation, increased survival of dopaminergic neurons, and improved locomotor functions. In summary, GDNF-transfected macrophages represent a promising therapeutic strategy for PD at both late- and early-stages of the disease.

Original languageEnglish (US)
Pages (from-to)139-149
Number of pages11
JournalJournal of Controlled Release
Volume315
DOIs
StatePublished - Dec 10 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019

Keywords

  • GDNF
  • Macrophages
  • Neuroinflammation
  • Parkinson's disease
  • Transgenic mice

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