Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS

Mol Ther. 2008 Dec;16(12):2002-10. doi: 10.1038/mt.2008.197. Epub 2008 Sep 16.


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which there is a progressive loss of motor neurons and their connections to muscle, leading to paralysis. In order to maintain muscle connections in a rat model of familial ALS (FALS), we performed intramuscular transplantation with human mesenchymal stem cells (hMSCs) used as "Trojan horses" to deliver growth factors to the terminals of motor neurons and to the skeletal muscles. hMSCs engineered to secrete glial cell line-derived neurotrophic factor (hMSC-GDNF) were transplanted bilaterally into three muscle groups. The cells survived within the muscle, released GDNF, and significantly increased the number of neuromuscular connections and motor neuron cell bodies in the spinal cord at mid-stages of the disease. Further, intramuscular transplantation with hMSC-GDNF was found to ameliorate motor neuron loss within the spinal cord where it connects with the limb muscles receiving transplants. While disease onset was similar in all the animals, hMSC-GDNF significantly delayed disease progression, increasing overall lifespan by up to 28 days, which is one of the largest effects on survival noted for this rat model of FALS. This preclinical data provides a novel and practical approach toward ex vivo gene therapy for ALS.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology*
  • Amyotrophic Lateral Sclerosis / therapy
  • Animals
  • Cell Survival
  • Cell- and Tissue-Based Therapy
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Genetic Therapy
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Humans
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / metabolism*
  • Motor Neurons / cytology*
  • Motor Neurons / metabolism*
  • Muscles / metabolism*
  • Mutation / genetics
  • Neuroglia / metabolism
  • Neuromuscular Junction / genetics
  • Neuromuscular Junction / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Survival Rate


  • Glial Cell Line-Derived Neurotrophic Factor
  • SOD1 protein, human
  • Sod1 protein, rat
  • Superoxide Dismutase
  • Superoxide Dismutase-1