Stem cells nestle in the brain

First-of-its-kind clinical trials for the treatment of severe brain injury with stem cells arouse great interest in the scientific community and raise the level of ambition of the new and promising treatments. New hope for patients with serious and incurable diseases?

Charles Choi, Scientific American

The first clinical tests of their kind for the treatment of severe brain damage, chronic stroke, with the help of stem cells may begin this year. This depends on the approval by the US Food and Drug Administration (FDA) of an application submitted in December 2006 by the stem cell company ReNeuron (ReNeuron) of Guilford, England. Tests show that not only is the number of treatments using stem cells increasing, but their degree of ambition is also increasing. Chronic stroke, in which the sufferers suffer permanent damage, is the leading cause of disability in adults in developed countries. 25 million people worldwide suffer from chronic stroke, and the number of new cases increases by 7% each year, mainly because the population is aging. "Currently there are almost no ways to treat chronic stroke, and the available ways focus on the symptoms and not the cause," says neurologist Justin Zivin of the University of California, San Diego.

Stem cells are able to regenerate body parts. In previous animal stroke studies, stem cells injected into the brain or bloodstream migrated to the areas of injury, apparently in response to signals sent by the damaged cells. This migration may occur because the repair pathways activated by the damaged cells are similar to pathways used in embryonic development, in which stem cells play a central role, explains John Sinden, co-founder and chief scientist of Re-Neuron.

Make the cells stable 

One of the main problems with stem cells is related to their instability when grown in the laboratory. Re-Neuron can produce a large number of stable cell lines by inserting a transgenic version of the c-myc gene. This gene encourages cell division and activates other genes that prevent the formation of defects in chromosomes. The scientists can activate or deactivate c-myc at will by adding or inhibiting a synthetic compound.
Re-Neuron developed cells to treat brain damage by inserting the engineered version of c-myc into human fetal brain tissue taken from a US cell bank. They tested the stability and durability of 120 neural stem cell lines in the laboratory. They also tested which cells could be transplanted into animals without provoking a rejection reaction from the immune system. Two cell lines looked promising: ReN001, intended for the treatment of stroke, and ReN005, which is being tested for the treatment of Huntington's disease.
In studies of stroke-prone rats, treatment with ReN001 significantly improved sensory and motor function. Sinden clarifies that the stem cells probably did not replace the huge amount of cells lost during the stroke. More likely they secreted substances that activated repair pathways to create new blood vessels and brain cells.

The next step: an experiment on ten patients
If the first phase of the clinical trials, which examines the drug's safety and initial effectiveness, is approved, researchers from the University of Pittsburgh will test the treatment on 10 patients suffering from chronic ischemic stroke, the most common form of stroke, in which a blood clot obstructs blood flow. Ten to twenty million cells will be transplanted directly into the brain through a small hole in the skull, and the patients will be monitored for the next 24 months. Re-Neuron is working with BioReliance in Glasgow, Scotland, to produce a large amount of cells. The company currently has about a million ReN001 doses, Sinden estimates.
Clinical trials that preceded this and tested stem cell treatments for chronic stroke patients, used cells derived from human tumors or brain tissue from pig embryos. Re-neuron embryonic cells "resemble neurons in (healthy) people more than earlier cells, so they may be more efficient," Zivin says.
"The process Re-Neuron has developed to produce the cell lines is ambitious and well thought out," says neuroscientist Sean Savitz of Harvard Medical School. But Savitz adds and says that the c-myc gene is related not only to development and stem cells but also to cancer. "It is not intended to say that it will encourage cancerous tumors," he says, but the researchers "will have to continue to convince the scientific community that the cells will not undergo uncontrolled division as they do in cancerous tumors."