A study coordinated by Lorenz Studer, a NEUROSTEMCELL principal investigator, has developed a new strategy for the efficient transformation of human pluripotent stem cells (PSCs) into dopamine-producing neurons. The neurons can be implanted into animals where they show “robust performance” by forming new connections and achieving long-term survival. The result is a significant progress in the use of PSCs and may help to develop new therapies for neurodegenerative diseases. The work is published in the journal Nature.
The degeneration of dopamine-producing (dopaminergic, in jargon) neurons is the main event behind the onset of Parkinson disease. One goal of NEUROSTEMCELL is to use PSCs to produce dopaminergic neurons that may be transplanted in patients affected by Parkinson’s and other neurodegenerative disorders.
Over the last decade, several groups have obtained dopaminergic-like cells from embryonic stem cells in a culture dish. However, those cells fell short of behaving like normal dopaminergic neurons. For example, they did not survive long enough after transplantation and often multiplied abnormally, leading to neural overgrowth and, sometimes, cancer.
Studer and his coworkers harnessed insights from developmental biology to overcome these problems. They developed a strategy to obtain “authentic” dopaminergic cells that are very similar to the ones normally found in the brain.
When researchers implanted these new cells into animal models of Parkinson disease — mice, rats and monkeys — the neurons survived and integrated properly in the brains, and produced dopamine like their normal counterparts. Also, they did not multiply abnormally after transplantation, which avoided neural overgrowth and adverse events following engraftment in the animals. The treatment also improved some symptoms in Parkinson’s affected rodents.
The results are encouraging but are still in the field of basic research, warn the authors of the Nature study. More work is needed before these findings may be eventually transferred to patients. “We are now gearing up to produce dopaminergic cells under conditions that would be suitable for clinical use. The process involves careful adaptations in cell manufacturing, scale up and safety testing. We expect completion of those studies within the next 3-4 years, the minimum time frame required for initiating studies potentially in human patients”, says Studer.
“We are very fortunate to be the only non-EU member of Neurostemcell [...]. My lab has greatly benefited from the collaborative and interactive environment, and the shared mission helped in driving the project forward”, he says.
Sonja Kriks, Jae-Won Shim, Jinghua Piao, Yosif M. Ganat, Dustin R. Wakeman, Zhong Xie, Luis Carrillo-Reid, Gordon Auyeung, Chris Antonacci, Amanda Buch, Lichuan Yang, M. Flint Beal, D. James Surmeier, Jeffrey H. Kordower, Viviane Tabar & Lorenz Studer. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature, 6 November 2011 (online) doi:10.1038/nature10648
Elena Cattaneo, University of Milan, NeuroStemcell coordinator:
This work represents an important step towards the possible application in the clinic of human embryonic stem cell based therapies and sets a challenge for Europe concerning the future regulatory ground and the competitiveness of regenerative medicine.
Anders Björklund, Lund University, Sweden and NeuroStemcell deputy coordinator:
The new study represents an important step in the development of a stem cell based therapy for Parkinson´s disease. Efforts along these lines go back to the late 1980s when the first patients received transplants of dopamine neurons derived from the developing brain of aborted fetuses. Although these trials have given quite promising results in some patients, the use of fetal tissue for cell transplantation is both ethically and practically problematic. Over the last decade, therefore, the focus of research has been on the use of stem cells for this purpose. The generation of fully functional dopamine neurons in large numbers, however, has turned out to be a challenge. Previous attempts have faced two major hurdles: to get the stem cell derived dopamine neurons to survive and grow in the recipient brain, and to avoid the inclusion of dividing cells that overgrow to form tumors. The derivation technique devised by the Studer team in this new study is a breakthrough in this regard: their procedure is not only remarkably efficient, but the neurons generated show excellent survival and provide efficient restoration of motor deficits in both rodent and primate transplantation models.
Austin Smith, University of Cambridge, NeuroStemcell PI:
The European Commission have played an important role by part-funding the research. This means the results have been shared at an early stage with European scientists who are now working towards applications in patients together with Dr Studer.
Read the press release from Nature