Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration

A therapeutic strategy for parkinson's disease

Kc Biju, Qing Zhou, Guiming Li, Syed Z. Imam, James Roberts, William W. Morgan, Robert A Clark, Senlin Li

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Glial cell line-derived neurotrophic factor (GDNF) has emerged as the most potent neuroprotective agent tested in experimental models for the treatment of Parkinson's disease (PD). However, its use is hindered by difficulties in delivery to the brain due to the presence of the blood-brain barrier (BBB). In order to circumvent this problem, we took advantage of the fact that bone marrow stem cell-derived macrophages are able to pass the BBB and home to sites of neuronal degeneration. Here, we report the development of a method for brain delivery of GDNF by genetically modified macrophages. Bone marrow stem cells were transduced ex vivo with lentivirus expressing a GDNF gene driven by a synthetic macrophage-specific promoter and then transplanted into recipient mice. Eight weeks after transplantation, the mice were injected with the neurotoxin, MPTP, for 7 days to induce dopaminergic neurodegeneration. Macrophage-mediated GDNF treatment dramatically ameliorated MPTP-induced degeneration of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra and TH + terminals in the striatum, stimulated axon regeneration, and reversed hypoactivity in the open field test. These results indicate that macrophage-mediated GDNF delivery is a promising strategy for developing a neuroprotective therapy for PD.

Original languageEnglish (US)
Pages (from-to)1536-1544
Number of pages9
JournalMolecular Therapy
Volume18
Issue number8
DOIs
StatePublished - Aug 2010

Fingerprint

Glial Cell Line-Derived Neurotrophic Factor
Parkinson Disease
Macrophages
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Tyrosine 3-Monooxygenase
Blood-Brain Barrier
Bone Marrow Cells
Stem Cells
Therapeutics
Lentivirus
Neurotoxins
Brain
Neuroprotective Agents
Substantia Nigra
Axons
Regeneration
Theoretical Models
Transplantation
Neurons
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration : A therapeutic strategy for parkinson's disease. / Biju, Kc; Zhou, Qing; Li, Guiming; Imam, Syed Z.; Roberts, James; Morgan, William W.; Clark, Robert A; Li, Senlin.

In: Molecular Therapy, Vol. 18, No. 8, 08.2010, p. 1536-1544.

Research output: Contribution to journalArticle

Biju, Kc ; Zhou, Qing ; Li, Guiming ; Imam, Syed Z. ; Roberts, James ; Morgan, William W. ; Clark, Robert A ; Li, Senlin. / Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration : A therapeutic strategy for parkinson's disease. In: Molecular Therapy. 2010 ; Vol. 18, No. 8. pp. 1536-1544.
@article{a0b28895321d45fb9efc84f189809095,
title = "Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration: A therapeutic strategy for parkinson's disease",
abstract = "Glial cell line-derived neurotrophic factor (GDNF) has emerged as the most potent neuroprotective agent tested in experimental models for the treatment of Parkinson's disease (PD). However, its use is hindered by difficulties in delivery to the brain due to the presence of the blood-brain barrier (BBB). In order to circumvent this problem, we took advantage of the fact that bone marrow stem cell-derived macrophages are able to pass the BBB and home to sites of neuronal degeneration. Here, we report the development of a method for brain delivery of GDNF by genetically modified macrophages. Bone marrow stem cells were transduced ex vivo with lentivirus expressing a GDNF gene driven by a synthetic macrophage-specific promoter and then transplanted into recipient mice. Eight weeks after transplantation, the mice were injected with the neurotoxin, MPTP, for 7 days to induce dopaminergic neurodegeneration. Macrophage-mediated GDNF treatment dramatically ameliorated MPTP-induced degeneration of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra and TH + terminals in the striatum, stimulated axon regeneration, and reversed hypoactivity in the open field test. These results indicate that macrophage-mediated GDNF delivery is a promising strategy for developing a neuroprotective therapy for PD.",
author = "Kc Biju and Qing Zhou and Guiming Li and Imam, {Syed Z.} and James Roberts and Morgan, {William W.} and Clark, {Robert A} and Senlin Li",
year = "2010",
month = "8",
doi = "10.1038/mt.2010.107",
language = "English (US)",
volume = "18",
pages = "1536--1544",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration

T2 - A therapeutic strategy for parkinson's disease

AU - Biju, Kc

AU - Zhou, Qing

AU - Li, Guiming

AU - Imam, Syed Z.

AU - Roberts, James

AU - Morgan, William W.

AU - Clark, Robert A

AU - Li, Senlin

PY - 2010/8

Y1 - 2010/8

N2 - Glial cell line-derived neurotrophic factor (GDNF) has emerged as the most potent neuroprotective agent tested in experimental models for the treatment of Parkinson's disease (PD). However, its use is hindered by difficulties in delivery to the brain due to the presence of the blood-brain barrier (BBB). In order to circumvent this problem, we took advantage of the fact that bone marrow stem cell-derived macrophages are able to pass the BBB and home to sites of neuronal degeneration. Here, we report the development of a method for brain delivery of GDNF by genetically modified macrophages. Bone marrow stem cells were transduced ex vivo with lentivirus expressing a GDNF gene driven by a synthetic macrophage-specific promoter and then transplanted into recipient mice. Eight weeks after transplantation, the mice were injected with the neurotoxin, MPTP, for 7 days to induce dopaminergic neurodegeneration. Macrophage-mediated GDNF treatment dramatically ameliorated MPTP-induced degeneration of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra and TH + terminals in the striatum, stimulated axon regeneration, and reversed hypoactivity in the open field test. These results indicate that macrophage-mediated GDNF delivery is a promising strategy for developing a neuroprotective therapy for PD.

AB - Glial cell line-derived neurotrophic factor (GDNF) has emerged as the most potent neuroprotective agent tested in experimental models for the treatment of Parkinson's disease (PD). However, its use is hindered by difficulties in delivery to the brain due to the presence of the blood-brain barrier (BBB). In order to circumvent this problem, we took advantage of the fact that bone marrow stem cell-derived macrophages are able to pass the BBB and home to sites of neuronal degeneration. Here, we report the development of a method for brain delivery of GDNF by genetically modified macrophages. Bone marrow stem cells were transduced ex vivo with lentivirus expressing a GDNF gene driven by a synthetic macrophage-specific promoter and then transplanted into recipient mice. Eight weeks after transplantation, the mice were injected with the neurotoxin, MPTP, for 7 days to induce dopaminergic neurodegeneration. Macrophage-mediated GDNF treatment dramatically ameliorated MPTP-induced degeneration of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra and TH + terminals in the striatum, stimulated axon regeneration, and reversed hypoactivity in the open field test. These results indicate that macrophage-mediated GDNF delivery is a promising strategy for developing a neuroprotective therapy for PD.

UR - http://www.scopus.com/inward/record.url?scp=77955171756&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955171756&partnerID=8YFLogxK

U2 - 10.1038/mt.2010.107

DO - 10.1038/mt.2010.107

M3 - Article

VL - 18

SP - 1536

EP - 1544

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 8

ER -