Neurons, our brain cells, do not regenerate during our life. This makes neurodegenerative diseases, such as Parkinson's and Huntington's, difficult to treat. To tackle such diseases, the NeuroStemCell project, funded by the EU, aims to develop stem-cell-based therapies. It focuses on getting a better understanding of neurons differentiation from two different kinds of stem cells—namely embryonic stem cells and induced pluripotent stem cells, both capable of being programmed to develop into neurons. Malin Parmar, a researcher in neurobiology at Lund University, Sweden, was one of the main partners in the project, which was completed in May 2013. She talks to youris.com about the challenges that lie ahead before scientists get one step closer to clinical applications.
Why are you studying how to regenerate or renovate the neurons themselves?
In Parkinson's disease dopamine neurons are lost. What we focused on was to generate such brain cells, starting from the human embryonic stem cells. The goal was to make them identical to the dopamine neurons you would find in a healthy brain. As the name suggests, dopamine neurons are the main source for dopamine and their loss is at the base of neurodegenerative diseases. The newly produced cells are the ones that you would transplant to the patients. They should take over the same functions of the dopamine neurons that are lost due to the disease.
You succeeded in producing new neurons from stem cells in vitro. Were you able to transplant them?
We transplanted these neurons produced in the laboratory into mouse and rat models of Parkinson's disease. The first thing we did was to introduce a toxin on one side of the brain to mimic a loss of brain capability. The kind of toxin we used selectively kills the dopamine neurons. This means that this approach mimics Parkinson's disease on one side of the brain. At this point, the animal has motor deficits in one half of the body, like a Parkinson's patient. Then, we transplanted the ‘new’ neurons. We succeeded in restoring the brain functions and the animal could recover. We showed that it is possible to transplant these brain cells into the animal model without the insurgence of tumors, which is one of the most common side effects in this kind of situation. The rats recovered the motor functions that were lost due to the disease and that was the case in the long-term.
What are the difficulties in transplanting the cells into a human being?
Before you can use such cells on patients, you need to establish a protocol for deriving the neurons from stem cells under the highest standards, a process called GMP, which stands for Good Manufacturing Practice. This protocol needs to be very well defined and reproducible which will produce well certified and validated cells. We already know how to do it on a small scale. Now, we just need to do it on a bigger scale, because you need many more cells for humans than for rats. We also need to produce them in facilities that can assure that the cells are always good quality. And, of course, you then have to test them on animal models again before you could use them with patients.
What are the main scientific results of the project?
We really are at the beginning of the understanding of how human embryonic stem cells become neurons. One of the main difficulties, during the project, was to control the differentiation of stem cells into subtext specific neurons. The inefficient differentiation and incomplete patterning of the cells created several problems. During the project, there were several key challenges that arose that ultimately allowed us to produce protocols for efficient generation of dopaminergic and striatal neurons from human embryonic stem cells.
What are the next steps?
The next step is mainly the upscale of the process for cell production. This is essential to progress toward an effective cure. There is a new EU-funded project, called NeuroStemCell Repair, which is closer to clinical use of the cells than ours. We have solved many of the key questions during our project. Now, the new one will focus on the translation of these findings into clinical use.
Apart from this new project network, which is partially different from the NeuroStemCell’s, there is another group, coordinated by Anne Rosser in Cardiff, working in the same field. They are focusing only on Huntington's disease, where a different cell type—the medium spiny neurons of the striatum—is lost in patients.