Last year, a research group based at Johns Hopkins University in Baltimore made headlines by injecting stem cells into rodents paralyzed by an ALS-like disease — and restoring movement.
Those experiments raised hopes that stem cells could be used to replace or repair the muscle-controlling nerve cells (motor neurons) damaged by ALS. But much work needs to be done before this cell therapy can be tested in people, said Jeffrey Rothstein, lead researcher on the experiments and co-director of the MDA/ALS Center at Johns Hopkins.
"We need to know: Are stem cells safe? Which ones are the best? How do you deliver them? How do they work, and what's the expected outcome?" Rothstein said.
Recently, scientists have begun to tackle those questions, and they've come up with some encouraging answers.
Are they safe?
The power of stem cells — their ability to divide and generate many different cell types — has many scientists worried that they could multiply uncontrollably and form tumors.
Rothstein's team, along with a group led by Ted Teng at Harvard Medical School in Boston, have begun to probe stem cell safety by shifting their experiments from rodents to animals that more closely resemble humans.
At the annual Society for Neuroscience meeting held in San Diego last month, the researchers showed they could give monkeys an ALS-like condition by injecting a plant-derived toxin called ricin into nerves in the monkeys' legs. The ricin kills motor neurons in the part of the spinal cord connected to those nerves, causing paralysis of the injected leg.
When the researchers injected stem cells into the fluid-filled space within the spinal cord, some of the cells appeared to incorporate into the spinal cord, and none appeared in other tissues far away from the site of delivery — a good sign that the cells won't disperse and form tumors.
"Six months after stem cell delivery, there's no obvious adverse effect. The cells don't do anything toxic to the spinal cord," Rothstein said.
"But what everyone really wants to know is: Did the cells do any good?" he admitted. "We do know there's some improvement in the physiological properties of the limb, but that's really not enough to hang our hat on yet."
Before moving to the clinic, Rothstein and other ALS researchers are also trying to figure out which stem cells pack the most punch for repairing the damaged spinal cord.
|One obvious way to use stem cells for ALS treatment would be to turn them into replacement neurons. Another option might be to save existing neurons by turning stem cells into astrocytes or blood cells.
Rothstein and Teng have tested different kinds of stem cells — from mice and humans, from different tissues and different stages of development — with various results.
At the SFN meeting, Teng reported that when human neural stem cells (those that will become nerve cells, or neurons) were transplanted into ricin-injected monkeys, the cells appeared to become neurons and make connections with other neurons in the spinal cord.
Another group, led by Alison Willing at the University of South Florida in Tampa, has been investigating human NT neurons — a laboratory-grown line of cells that aren't really stem cells, but can divide to produce neurons.
Willing's group transplanted those cells into the spinal cords of mice with the familial version of ALS, and found "striking results," she said. When treated early in the disease, the mice developed ALS one month later and lived two weeks longer than expected. When given to mice in advanced stages of ALS, the transplants didn't affect survival but slowed progression of the disease.
Human NT neurons are already FDA-approved for clinical trials in stroke patients, so they could be fast-tracked into ALS trials, Willing said.
Replacement vs. repair
Early in the course of stem cell research, many scientists envisioned using stem cells to replace cells that were lost to disease.
But Rothstein's first experiments in mice with ALS suggested that the transplanted cells weren't filling in for missing motor neurons. Instead, they seemed to help repair or protect motor neurons that were at death's door.
Given that insight, many ALS researchers are probing stem cells for their ability to become other cell types that might stave off neuronal damage.
Robert Brown, director of the MDA/ALS Center at Massachusetts General Hospital in Boston, is investigating the use of stem cells derived from human umbilical cords. Those cells can probably become neurons, as well as a number of other cell types, including red blood cells and white blood cells (immune cells).
At the International Symposium on ALS/Motor Neuron Disease held in Oakland, Calif., in November, Brown reported that a simple intravenous injection of the "cord blood" cells prolonged survival in mice with familial ALS. The cells' mode of action isn't clear — given recent evidence linking ALS to autoimmunity (a self-directed attack of the immune system), there's speculation that they might have worked by revamping the immune system.
MDA grantee Nicholas Maragakis of Johns Hopkins is taking another approach, using cells called glial-restricted precursors. Those cells are destined to become astrocytes — cells in the brain and spinal cord that nourish and protect neurons, in part by shielding them from the potentially toxic brain chemical glutamate.
At the SFN meeting, Maragakis reported that by transplanting glial-restricted precursors into a piece of rat spinal cord, he could protect motor neurons in the cord from an overexposure to glutamate. Soon, he plans to test the cells in mice with ALS.
"It's an entirely different approach," Maragakis said. "It combines stem cells with what we know about glutamate as a toxin. We're interested in protecting neurons that are still there because we think that's easier than trying to replace neurons that are dead."