Non-viral gene delivery of the GDNF, either alone or fused to the C-fragment of tetanus toxin protein, prolongs survival in a mouse ALS model

Restor Neurol Neurosci. 2012;30(1):69-80. doi: 10.3233/RNN-2011-0621.


Purpose and background: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease with no effective therapy. Glial-cell line derived neurotrophic factor (GDNF) has been translated to clinical trials for treatment of ALS and its selective delivery to the motoneurons could improve its therapeutic abilities.

Methods: To test this idea, we genetically fused GDNF to the C-fragment of tetanus toxin (TTC), a peptide able to specifically deliver molecules to motoneurons.

Results: Single intramuscular administration of naked-DNA encoding GDNF or GDNF-TTC significantly delayed the onset of symptoms and functional deficits into the SODG93A mouse model of ALS, prolonging their lifespan.

Conclusions: We have demonstrated a neuroprotective effect of GDNF-TTC as shown by the activation of survival pathways and inhibition of apoptotic proteins, such as Akt phosphorylation, or reduced caspase-3 activation respectively. However, the GDNF fusion with TTC did not improve the therapeutic effects when compared to GDNF alone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Age of Onset
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / therapy*
  • Analysis of Variance
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Caspase 3 / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Growth Factors / biosynthesis
  • Nerve Growth Factors / therapeutic use*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Peptide Fragments / therapeutic use*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Superoxide Dismutase / genetics
  • Tetanus Toxin / genetics
  • Tetanus Toxin / metabolism
  • Tetanus Toxin / therapeutic use*


  • CDNF protein, human
  • Nerve Growth Factors
  • Peptide Fragments
  • Tetanus Toxin
  • tetanus toxin fragment C
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Proto-Oncogene Proteins c-akt
  • Caspase 3