Maximising the prospects for successful clinical trials of stem-cell therapy for neurodegenerative diseases such as Huntington's and Parkinson's is proving possible through co-operation between experimental and clinical researchers
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How is it possible to rewind life and take cells back to their embryonic state? The answer may be stem-cell generation and regenerative medicine.

This field of science for medical treatment is at the forefront of technology and therapeutics – and it is controversial. The potential to replace damaged cells in the brain, and even to enable recovery of lost functions, in devastating conditions such as Parkinson’s disease and Huntington’s disease holds amazing hope for those affected.

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The scientists involved in the NeuroStemCell project, the European Consortium for Stem Cell Therapy in Neurodegenerative Diseases, are faced with the daily challenge of big unanswered questions, together with pressing ethical issues. The NeuroStemCell project is part of the European FP7 programme, with a total cost of almost €16 million – with the European Union contributing almost €12 million of this funding.

NeuroStemCell was formed to create a world-leading consortium that can take stem cell based therapies for Parkinson’s disease (PD) and Huntington’s disease (HD) to the clinic. The consortium brought 13 together elite European research teams and three SMEs from six EU member countries, with the goal to develop safe and validated cells and clinical-grade reagents to be used in clinical trials and eventually also in drug discovery.

PLURIPOTENT CELLS

Parkinson’s disease and Huntington’s disease are both responsible for the death of specific neurons in the brain and for a progressive loss of cognitive and motor functions. A tantalising new future can, however, be opened up if brand-new cells can be grown with the potential to become the type of cell that is needed to repair damaged organs. These are so-called ‘pluripotent cells’ and they lie at the heart of stem-cell research. Embryonic stem cells have so far proved to be the purest form of natural stem-cell material.

The Nobel Prize in Physiology or Medicine for 2012 was awarded jointly to Sir John B. Gurdon and Shinya Yamanaka “for the discovery that mature cells can be reprogrammed to become pluripotent”. These are induced pluripotent stem cells (IPSCs), with the potential to regenerate diseased or damaged tissues for an individual patient, using their own adult cells as the source material. At this stage, however, many vital pieces of information are still unknown and the investigation of the therapeutic potential of IPSCs in animals is still at an early stage.

PD and HD are ideal candidate diseases for restorative stem cell-based therapies. In both diseases, the pathology is slowly progressive and characterized by the preferential loss of one type of neuron, i.e., the mesencephalic dopamine (mesDA) neurons in PD and the GABAergic medium-sized spiny neurons in HD. The cell-replacement strategy aims at substituting the lost mesDA and GABA neurons, respectively, by implantation of new functional cells. Although other cell types are ultimately affected, experimental evidence obtained in rodent and primate models of PD and HD, as well as the experience gained from clinical trials using grafts of fetal mesDA and striatal GABAergic progenitors, indicate that effective restorative therapies may be possible to achieve by neural transplantation in these two diseases. Further development of this approach, however, will critically depend on the development of alternative sources of therapeutically effective cells derived from stem cells.

NeuroStemCell is focused on the identification and systematic comparison of progenitor cell lines with the most favourable characteristics for mesDA and striatal GABAergic neuronal differentiation, generated either directly from human embryonic stem (ES) cells, from neural stem cells derived from ES cells, from induced pluripotent stem cells or from in vitro short-term expanded neural progenitors from ventral midbrain grown as neurospheres. It performs rigorous and systematic testing of the most prominent candidate cells in appropriate animals models.

The project is dealing with some of the biggest and most fascinating issues and questions. Firstly, what is the best possible way to produce pure stem cells? Is it even possible to take adult cells back in time, as it were, to an embryonic state and start development afresh? Could treatment make use of a ‘cell bank’ at an intermediate stage of development? How can we generate a sufficient quantity of high-quality material that remains stable over time and does not lose any of its purity?

As NeuroStemCell faces these fascinating issues, the project is rooted in sound, thorough procedures aimed at taking a completely fresh look at the best possible source of stem-cell material for the future. There are numerous steps involved in creating neurons that can reliably replace those damaged by Parkinson’s or Huntington’s.

DEVELOPING THE NERVOUS SYSTEM

As the project co-ordinator, Professor Elena Cattaneo at the Università degli Studi di Milano in Italy is bringing together a whole range of studies to achieve this massive goal, including work to mimic the development of the nervous system and ways of instructing stem cells to become neurons, which in turn requires new expertise in transplanting cells. Here are just some of the programmes within the project.

  • In Lund, Sweden, a team led by Professor Anders Bjorklund, deputy coordinator of NeuroStemCell, is specialising in generating pure populations of cells to be used in cell replacement therapy for Parkinson’s and establishing safe methods of grafting cells that survive and function in the long term.
  • In Cambridge, UK, Professor Austin Smith is identifying what determines pluripotency, while Professor Roger Barker and his Transneuro Consortium are focusing on taking transplant procedures for injecting cells into the brains of Parkinson’s patients to a new level of reliability.
  • In New York, USA, Dr Lorenz Studer is investing years of scientific expertise and financial resources into producing dopamine cells required to treat Parkinson’s that stay stable after transplantation and therefore enable sustained recovery of lost functions.
  • In Bonn, Germany, Professor Oliver Brüstle is researching embryonic and IPCS cells to produce stem cell material from an intermediate stage of cell development or ‘cell bank’.
  • On yet another front, Professor Cattaneo and her team in Milan are using the same techniques to develop sources of striatal neurons, specific cells required to treat Huntington’s disease.

Given the broad range of cutting-edge research that is involved in the project, it is easy to see why the partners are so motivated by the NeuroStemCell project. There is no room here for those who prefer to go it alone; the partners know they need to build on each element of the project as they create safe and transplantable cells that are increasingly authentic and offer stable, long-term qualities beyond transplantation.

The project started in December 2008 and was due to finish in May of this year, but the co-ordinators applied for a six-month extension because there were so many exciting strands to this research that could yield more results with just some extra time. Work towards generating pure populations of cells and advancing transplant techniques, for example, are now set to progress towards clinical trials.

© European Union, 2013

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  How is it possible to rewind life and take cells back to their embryonic state? The answer may be stem-cell generation and regenerative medicine. This field of science for medical treatment is at the forefront of technology and therapeutics – and it is controversial. The potential to replace damaged cells...