Wise Young
09-21-2005, 04:12 AM
The authors genetically modified human neural stem cells to produce GDNF and transplanted them into rats that express the ALS gene SOD1. The cells survived and integrated into the spinal cord, secreted GDNF, and produced changes in cholinergic expression of motoneurons around the transplants.
Klein SM, Behrstock S, McHugh J, Hoffmann K, Wallace K, Suzuki M, Aebischer P and Svendsen CN (2005). GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum Gene Ther 16: 509-21. 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. Waisman Center and Department of Anatomy, University of Wisconsin, Madison, WI 53703, USA. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15871682
Klein SM, Behrstock S, McHugh J, Hoffmann K, Wallace K, Suzuki M, Aebischer P and Svendsen CN (2005). GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum Gene Ther 16: 509-21. 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. Waisman Center and Department of Anatomy, University of Wisconsin, Madison, WI 53703, USA. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15871682