BioWorld International Correspondent
LONDON - A newfound ability to stimulate embryonic stem cells to turn into dopamine-producing neurons has the potential to revolutionize treatments for Parkinson's disease.
People with Parkinson's disease suffer symptoms such as tremors, due to the loss of dopamine-producing neurons in the midbrain.
As well as paving the way toward therapies that involve transplanting dopamine-producing cells into the brains of sufferers, the breakthrough suggests that the biotech industry now has an unlimited supply of those cells on which to test candidate drugs.
Johan Ericson, professor of developmental biology at the Karolinska Institute in Stockholm, Sweden, told BioWorld International: "The importance of our discovery is that we provide a new tool to allow people to generate dopaminergic neurons with an authentic mid-brain identity. What is more, we can generate these cells efficiently. This is a vital step toward testing whether transplantation therapy for Parkinson's disease will ever become clinically important."
Ericson, together with Thomas Perlmann, who is professor of molecular developmental biology, also at the Karolinska Institute, reported the work on murine cells in the Jan. 27, 2005, issue of Cell in a paper titled "Identification of Intrinsic Determinants of Midbrain Dopamine Neurons."
The researchers have applied for a patent and are discussing licensing agreements with biotechnology companies.
Work to find out whether the cultured dopaminergic neurons can treat Parkinson's disease in a rat model of the disease already is under way. Initial results, Ericson said, are "extremely promising."
He also is confident that there will be few difficulties in carrying out the same transformation of human embryonic cells into dopaminergic neurons using the protocol the team has used for murine cells. "It is just a matter of time," Ericson said.
Almost 20 years ago, other Swedish researchers conducted studies that proved it was possible to treat Parkinson's disease by transplanting the right kind of dopamine-producing neurons into the brain. But the cells they used came from the brains of aborted fetuses, prompting both practical and ethical concerns. Nevertheless, in some patients, that treatment brought about a long-term improvement in symptoms.
More recently, scientists have pursued taking embryonic stem cells, which they have attempted to induce to differentiate into whatever type of cell is needed to treat disease - whether it is insulin-producing beta cells to replace those failing in the pancreas, or cartilage cells to produce new parts for injured joints.
Perlmann and Ericson, likewise, set out to establish how to turn embryonic stem cells into dopaminergic neurons. Perlmann said they decided to "learn from developmental biology," and they wanted to discover how the neurons normally develop in the embryo. If they could find the genes and factors responsible for inducing the neurons, then by adding those to the embryonic stem cells, they "might be able to recapitulate the developmental process."
The investigations identified a gene called Lmx1a as a "master determinant." Its product is, Ericson explained, "both sufficient and required for the generation of dopamine neurons during embryonic development.
"Simply taking this one gene and putting it into embryonic stem cells from mice, we can recapitulate the program of dopamine cell generation in vitro. This results in the production of a cell type that many people have been trying to generate previously," Ericson said.
Tests showed that the cells are of the exact type that is lost from the brains of those with Parkinson's disease.
Perlmann said: "In the use of stem cells for therapy, it is of utmost importance to make the correct cell type. In the brain, there are at least 1,000 different types of neurons, only one of which is clinically relevant to Parkinson's disease."
For the pharmaceutical industry, Ericson predicted, the bonus provided by the work will be the availability of unlimited quantities of dopaminergic neurons. Researchers will be able to investigate in detail the factors that contribute to the deaths of these cells and, more importantly, what small molecules might be able to interfere with the process and keep the cells alive.