UW-Madison rat experiment could lead to stem-cell treatment for ALS

UW-Madison rat experiment could lead to stem-cell treatment for ALS

Madison, Wis. — Scientists at the University of Wisconsin-Madison have sucessfully injected stem cells into rats’ spines in a way that could lead to treatments for degenerative diseases – but they did not use the controversial embryonic stem cells.
The researchers inserted human stem cells derived from fetal brain tissue into the spinal cords of rats afflicted with ALS, a disease that damages the nervous system. Their findings appeared this week in the journal Human Gene Therapy. The ALS Association and the UW Foundation supported the project.
Using a delivery method that may one day help to treat diseases such as amyotrophic lateral sclerosis, or ALS, a team including Clive Svendsen of the university’s Waisman Center directed certain types of neural stem cells to secrete a neuron-protecting protein before injecting them into the rat spinal cords, where motor neurons reside.
Motor neurons relay messages from the spinal cord and brain to the rest of the body. ALS progressively decays and kills those neurons.

Why this research is different

This particular team of researchers did not work with human embryonic stem cells, the blank-slate cells that arise during the earliest stages of development to form the 220 tissue and cell types in human beings. Instead, the scientists worked with more specialized neural progenitor cells, which the team collected from brain tissue supplied by the Birth Defects Research Laboratory in Seattle, which supplies tissue from electively aborted human fetuses.
Unlike embryonic stem cells, the progenitor cells can only develop into neural tissue and are incapable of living indefinitely, as embryonic stem cells can. But the progenitor cells are much more appropriate for clinical use because, unlike embryonic stem cells, they can grow without animal derivatives that are considered a potential source of contamination, Svendsen said.
“This is the first study that shows that certain types of stem cells can survive and release powerful protective proteins in the spinal cord of rats with a genetic form of ALS,” Svendsen said in a release.
Once inside the brain or spinal cord, neural progenitor cells grow into neuron-supporting stem cells called astrocytes. Some researchers believe that ALS causes astrocytes to malfunction, which in turn causes motor neurons to degenerate and eventually die.
Several research groups around the world are working with neural progenitor cells. But his team’s work is the first “double whammy,” Svendsen said, because the injected neural progenitor cells not only replace damaged cells but help protect existing motor neurons.
The protein that actually protects the motor neurons is called GDNF, for glial cell-line derived neurotrophic factor.
“The approach we’re taking is a protective approach versus a cell-replacement approach,” said Sandra Klein, lead author of the study and a UW-Madison doctoral researcher. “Embryonic stem cell research is important, because you can generate many different cell types, and in doing that, you can generate functional, mature neurons that you can hopefully transplant in the future.
“However, in neuro-degenerative diseases, when the cells die you also lose the circuitry involved in where the cells were originally, so you lose those connections to the outside world,” she added. “What we’re trying to do is protect neurons from dying in the first place. So they’re still connected to the muscle, and we’re just keeping them alive longer. And also maybe some neurons that had started to degenerate but are not fully lost can be rejuvenated and maybe reconnect with the muscle.”

How it works

Each year about 5,600 people in the United States are diagnosed with ALS. The disease attacks nerve cells in the brain and spinal cord; as motor neurons progressively die, the brain cannot initiate and control muscle movement.
The UW-Madison researchers tackled several technical barriers trying to ensure that the progenitor cells correctly gathered near the motor neurons in the spinal cord while continuing to pump GDNF once they got there, said Klein in a release.
Making GDNF-emitting stem cells was the team’s first hurdle. Svendsen and his team approached the problem using a genetically engineered viral structure known as a lentivirus. Collaborating with a researcher in Switzerland, the scientists manipulated the lentivirus’ genes, directing it to secrete GDNF. The team then infected neural progenitor cells with the lentivirus; once the cells were infected, the scientists washed the virus away, leaving self-sustaining colonies of GDNF-producing progenitor cells.
The next problem was actually getting the cells into the right location of the ALS rat spinal cord. “Nobody had shown that human progenitors could be delivered right into the region of the dying motor neurons,”  Klein said in the release. Klein bored into the base of a rat’s spine using a micro-pipette, or tiny dropping device, to deliver the progenitor cells into the bottom region of the spinal cord where motor neurons are located. After months of trial and error, Klein finally discovered through staining tests that the progenitor cells were indeed gathering near the neurons and releasing GDNF in the area.
Svendsen says the approach could be regarded as a novel form of gene therapy where progenitor cells are used as “mini-pumps” to deliver protein. The important thing now is to see whether greater numbers of GDNF-bearing progenitor cells can actually prolong the life of an ALS-ridden rat, Svendsen said. If so, he aims to plan a human safety trial with a small group of patients.

Human trials?

Klein said that Svendsen is consulting with the Food and Drug Administration on what needs to be done to go ahead with human trials. The team should be able to put cells into human patients within two to three years, she said.
Ordinarily, the researchers would first test the work in primates. However, “it’s such a horrible disease that it’s unethical for primates to be given this disease,” Klein told WTN. “So basically there’s no other model besides the rodent. So one thing that may need to be done is [using] larger mammals – just putting in stem cells into the spinal cord of a pig, for example, just to see where stem cells go, because a rat spinal cord is so much smaller than a human’s.”

Lincoln Brunner is a WTN contributing editor and can be reached at lincoln@wistechnology.com.