Human Neural Stem Cells Persist and Influence Nerve Cells in Rat Model of ALS
April 21, 2005
[QUICK SUMMARY: ALSA funded researchers placed genetically engineered human stem cells into rat spinal cord and showed that they can secrete, as instructed, a maintaining factor that aids the ability of nerve cells to function.]
Researchers at the Waisman Center in Madison, Wisconsin published, in the April 2005 issue of the journal Human Gene Therapy, encouraging findings in rats modeling amyotrophic lateral sclerosis (ALS). They showed that human stem cells can integrate into the critical area of the spinal cord that supplies the nerves that control muscles. This is the region where cells attacked by the disease process originate.
The stem cells, obtained from human fetal brain, are engineered to make a maintaining factor that supports nerve cells, and most likely turn into their surrounding helper cells called glia. The engineered cells survived as long as eleven weeks after the implant, and appear to integrate into the spinal cord neighborhood, and function.
The University of Wisconsin researchers, funded by The ALS Association (ALSA), are now testing treated rats to see if they retain motor function longer than untreated rats modeling the disease. The rats express the human gene for mutant SOD1, a change in a protein that is responsible for some inherited cases of ALS.
Clive Svendsen, Ph.D., the investigator directing the research, said that “we look forward to continual interactions with ALSA as we carefully take stem cells towards the clinic".
Svendsen noted that ALSA funding and sponsored forums with other stem cell and ALS researchers made it possible to move forward so rapidly with the strategy for treating the degenerative nerve disorder. “The help has not just been financial. From the start of the research, ALSA has also provided critical scientific insight and allowed participation of the investigators at key meetings where issues related to stem cell research and ALS have been discussed. The provision of the ALS rat has also been a vital component of this project,” Svendsen said.
Lucie Bruijn, Ph.D., ALSA science director, said “It is so exciting to see how rapidly ideas are moving from the laboratory into potential clinical application through strong collaborations with leading investigators. This has truly been a team approach.”
The stem cells are taken from the outer layers of human fetal brain. Growing in lab dishes, they are provided with a delivery system called a lentivirus vector. These viral molecules provide a gene for glial derived neurotrophic factor (GDNF).
The lentiviral construct was provided by collaboration with
GDNF is one of the so-called trophic factors that works in animal models of ALS, but may not reach the nervous system by itself in sufficient amounts for successful treatment of patients.
Engineered stem cells constantly producing human GDNF provide a way to specifically target the ailing nerve cells in ALS. Delivery of the modified stem cells was by precise injection into the spinal cord, a painstaking surgery carried out with a bit of trial and error by doctoral student and lead author Sandy Klein. The implant places a constant supply of the factor exactly where it is required.
The studies showed that GDNF is made only in the immediate area around the injection site.
The researchers saw that the rat spinal cord now had increased amounts of a marker for motor neurons. ALS relentlessly destroys motor neurons in the spinal cord and in the brain to produce progressive weakness, eventual paralysis, and death from respiratory failure when the motor loss finally involves the muscles that participate in breathing.
Svendsen acknowledged the important effort by all members of the research team and the funding sources, which include The Greater New York Chapter of ALSA, Michael Zaslow’s ZazAngels Fund, The Wisconsin Chapter of ALSA, The Harold L. Wilde ALS Research Fund, The Neil Brourman, M.D. ALS Research Fund and the Jack Orchard ALS Foundation.
“We would like to thank The ALS Association and its various chapters for their continual support of this work,” said Svendsen. “In particular the Evening of Hope fund raising event in Milwaukee in honor of Jeff Kaufman has been a continual inspiration for all of us working on this project.”
