GDNF delivery using human neural progenitor cells in a rat model of ALS

Hum Gene Ther. 2005 Apr;16(4):509-21. doi: 10.1089/hum.2005.16.509.


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of spinal cord, brainstem, and cortical motor neurons. In a minority of patients, the disease is caused by mutations in the copper (2+)/zinc (2+) superoxide dismutase 1 (SOD1) gene. Recent evidence suggests that astrocytes are dysfunctional in ALS and may be a critical link in the support of motor neuron health. Furthermore, growth factors, such as glial cell line-derived neurotrophic factor (GDNF), have a high affinity for motor neurons and can prevent their death following various insults, but due to the protein's large size are difficult to directly administer to brain. In this study, human neural progenitor cells (hNPC) isolated from the cortex were expanded in culture and modified using lentivirus to secrete GDNF (hNPC(GDNF)). These cells survived up to 11 weeks following transplantation into the lumbar spinal cord of rats overexpressing the G93A SOD1 mutation (SOD1 (G93A)). Cellular integration into both gray and white matter was observed without adverse behavioral effects. All transplants secreted GDNF within the region of cell survival, but not outside this area. Fibers were seen to upregulate cholinergic markers in response to GDNF, indicating it was physiologically active. We conclude that genetically modified hNPC can survive, integrate, and release GDNF in the spinal cord of SOD1 (G93A) rats. As such, they provide an interesting source of cells for both glial replacement and trophic factor delivery in future human clinical studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / therapy*
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Cell Survival
  • Cell Transplantation / methods
  • Disease Models, Animal
  • Genetic Therapy / methods*
  • Glial Cell Line-Derived Neurotrophic Factor
  • Humans
  • Motor Neurons / cytology
  • Motor Neurons / metabolism
  • Nerve Growth Factors / administration & dosage*
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Nerve Growth Factors / pharmacokinetics
  • Neurons / cytology
  • Neurons / physiology*
  • Rats
  • Rats, Mutant Strains
  • Spinal Cord / cytology
  • Stem Cells / cytology
  • Stem Cells / physiology*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1
  • Transplantation, Heterologous / methods


  • CAT development factor
  • GDNF protein, human
  • Gdnf protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • SOD1 protein, human
  • Sod1 protein, rat
  • Superoxide Dismutase
  • Superoxide Dismutase-1