The human central nervous system is a very advanced and extremely complex system. This system is also very vulnerable, due to its poor capacity for regeneration in adults. For example, a significantly damaged spinal cord does not recover.
“This applies to all mammals. It may be that evolution has led to this due to the stability required by a complex nervous system. Were neurons to constantly grow and establish new connections, the results could be chaotic. However, this stability becomes a problem when the central nervous system is injured,” Professor Heikki Rauvala explains.
Currently, there is not a single drug available to trigger regeneration in the central nervous system.
“Discovering such a drug is the eventual objective of our work,” he adds. “We want to find a way to fix damaged spinal cords.”
A drug that would bring about regeneration in the central nervous system would be a vast advancement for spinal cord injury patients, but in addition to that, there would be demand for such a drug in treating many disorders that degenerate the nervous system.
“Many diseases of the central nervous system, such as neurodegenerative diseases, traumatic brain injury and MS, destroy cells and their connections in the nervous system,” Rauvala points out.
“Bad guys” may turn out to be important allies
Rauvala has focused his investigations particularly on the saccharide structures found in the intercellular material and cell surfaces of neural tissue, liable to bind with, among others, growth factors and the proteins in the intercellular material and cell surfaces.
Chondroitin sulphates belonging to glycosaminoglycans are generally considered the cause for the non-regeneration of the central nervous system, since they inhibit neuron precursors from developing into neurons, as well as the establishment of connections between neurons.
However, Rauvala has observed that the role of chondroitin sulphates in the growth of the central nervous system is more complex than previously thought. Years ago, he isolated a protein that activates neuron growth and is expressed in the intercellular material of the central nervous system. Rauvala named his discovery HB-GAM (heparin-binding growth-associated molecule), which has later also become known as pleiotrophin. Investigating the protein more closely, Rauvala found that, in addition to heparin, it binds tightly with chondroitin sulphates.
“We noticed that HB-GAM is expressed in particularly large quantities in the intercellular material of the central nervous system at the time when the system is developing and still quite plastic. We started considering the importance of this phenomenon. Could HB-GAM, as it were, ‘override’ the inhibitory effect that chondroitin sulphates have on the growth of cells in the central nervous system?” Rauvala explains.
The researchers observed how brain cells behaved in cell cultures containing chondroitin sulphates, but no HB-GAM. The result was clear: no cell growth.
Next, HB-GAM was added to the culture.
“The brain cells started animatedly developing and growing a network of neurons!”
To their surprise, the researchers found that HB-GAM was not the only factor underlying this lively growth, but it was a matter of cooperation between it and chondroitin sulphate: if chondroitin sulphates were removed from the culture, leaving only the HB-GAM protein, growth was much weaker compared to both being present.
“Chondroitin sulphates are not, after all, solely the bad guys in this process.”
Motor functions in mice improved by the method
The results gained from cell cultures were inspiring, but would this method also work in a living organism? Disease models were the next step.
“We use a number of disease models to investigate the recovery of various types of spinal cord injury,” says Natalia Kulesskaya, a postdoctoral researcher.
The first findings have been promising: drug therapy has improved the performance of mice in tests requiring movement.
The research group has also been investigating the best method for administering the drug. Dosage into the bloodstream does not work, since the blood-brain barrier and the blood-cerebrospinal fluid barrier restrict the passage of many pharmacological substances into the central nervous system.
One option is to inject the drug directly into the area of injury. This method is practical and efficacious in situations where the injured area must in any case be operated on, making it unnecessary to perform a separate surgical procedure to administer the drug.
However, cases vary, which necessitates other methods of drug administration. Another alternative is lumbar puncture, the method used when collecting samples of cerebrospinal fluid.
“It turned out that this method works – we were able to prove that the drug injected into cerebrospinal fluid ended up in the injured area,” describes Kulesskaya.
“We know this works, now we just have to prove how it works.”
According to Rauvala, his group is the only one in the world taking this approach to repairing central nervous system damage.
“Methods based on the elimination of chondroitin sulphates or preventing their activity are already being investigated and developed in various locations, but we have a different approach: we are attempting to harness them for utilisation. We believe their activity can be steered to the desired direction. To this end, we are not only using HG-GAM, but also studying similar molecules that can achieve a similar effect.”
It was perhaps the unique approach of Rauvala’s group that impressed the assessors and decision-makers of the Wings for Life foundation, which funds research focused on curing spinal cord injury.
“Ours is admittedly an audacious project,” Rauvala and Kulesskaya concede.
“But we know that the approach we have developed is working! We have already demonstrated its feasibility in cell cultures and disease models. Now we still have to select the optimal drug candidate from among HB-GAM-type molecules and establish through immunohistochemical research methods that structural changes do actually occur in neural tissue. This is what we are currently doing. In two years, we hope to have data on this area as well to present to our funders.”