Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats

Mol Ther. 2008 Sep;16(9):1572-9. doi: 10.1038/mt.2008.146. Epub 2008 Jul 15.


Neuroinflammatory processes have been implicated in the progressive loss of ventral midbrain dopaminergic (DA) neurons that give rise to Parkinson's disease (PD), a late-onset movement disorder that affects 2% of the population over the age of 70 years. We have shown earlier, in two rat models of PD, that inhibition of the proinflammatory cytokine tumor necrosis factor (TNF) through nigral infusion of dominant-negative (DN-TNF) protein (XENP345) attenuates DA neuron loss. The objectives of this study were to develop a constitutive lentiviral vector encoding dominate-negative TNF, and to determine whether a gene therapy approach to deliver DN-TNF directly into the rodent substantia nigra could prevent or attenuate neurotoxin-induced DA neuron loss and associated behavioral deficits. Here we demonstrate that a single injection of lentivirus-expressing DN-TNF into rat substantia nigra, administered concomitant with a striatal 6-hydroxydopamine lesion, results in sufficiently high expression of inhibitor in vivo to attenuate both DA neuron loss and behavioral deficits resulting from striatal dopamine depletion. Our findings demonstrate the feasibility and efficacy of dominant-negative TNF gene transfer as a novel neuroprotective strategy to prevent or delay nigrostriatal pathway degeneration. This strategy holds the potential for therapeutic application in the treatment of PD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Behavior, Animal*
  • Brain / drug effects
  • Brain / metabolism
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cytoplasm / metabolism
  • Dependovirus / genetics
  • Female
  • Forelimb / drug effects
  • Forelimb / metabolism
  • Genes, Dominant / physiology*
  • Genetic Therapy*
  • Genetic Vectors
  • Green Fluorescent Proteins / metabolism
  • Immunoenzyme Techniques
  • Male
  • Nerve Degeneration / genetics
  • Nerve Degeneration / therapy*
  • Neurons / metabolism
  • Neurons / pathology
  • Oxidopamine / pharmacology
  • Parkinson Disease / genetics
  • Parkinson Disease / pathology
  • Parkinson Disease / therapy*
  • Protein Transport
  • Rats
  • Rats, Inbred F344
  • Rats, Sprague-Dawley
  • Substantia Nigra / metabolism*
  • Substantia Nigra / pathology
  • Transcription Factor RelA / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / therapeutic use*


  • Rela protein, mouse
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Oxidopamine
  • Amphetamine