Stem cell research could lead to new treatment strategies for motor neuron disease

The Motor Neurone Disease Association is funding its first ever stem cell research programme to help unlock the secrets of this fatal, neurological condition.

Pulling together world-class expertise from four leading researchers: Prof Siddharthan Chandran and Prof Sir Ian Wilmut from the University of Edinburgh; Prof Christopher Shaw from King's College London and Prof Tom Maniatis of Columbia University New York; the Association's groundbreaking programme will enable scientists, to perform detailed studies on human motor neurons containing known causes of motor neuron disease (MND).

The ability to grow and programme human motor neurons in the laboratory has been a holy grail for MND researchers for many years. Recent advances in stem cell research mean it is now possible to generate human motor neurons from donor skin cells in order to study the processes at work in health and disease.

MND kills five people everyday in the UK. Life expectancy for those with MND is short - around two to five years and around half of those diagnosed with MND die within 14 months. This cruel condition leaves people trapped in a failing body unable to walk, talk or feed themselves. There is no cure and no effective treatment. The cause of the disease is only known in 5% of all cases. Therefore the need to unlock the secrets of this devastating disease and progress research is imperative.

Dr Brian Dickie, director of research development at the MND Association, says: "The technology is now available to allow us to build upon the recent, important discoveries made by researchers around the world. We have started to make real progress in understanding the causes of motor neuron disease and further investigation is needed to maximise the potential of stem cells to find effective treatments and we hope eventually a cure.

"This international MND Association research programme will allow scientists to perform detailed studies on human motor neurons. As a result, we will be able to home in on the pivotal biochemical pathways that are altered in motor neuron disease, opening up promising new treatment strategies."

The principal aim of the Association's -800,000 three-year programme is to develop and characterise human brain cells, derived from the skin cells of MND patients with the hereditary TDP-43 form of the disease and also from 'control' donors who do not have MND and carry the normal TDP-43 gene.

The TDP-43 gene appears to be a direct cause of MND in around 1% of cases but the protein that the gene produces is found in up to 90% of MND cases. This discovery has been described as 'a seismic shift' in understanding the disease, as it points to TDP-43 playing a pivotal role in many forms of MND. The TDP-43 protein has also been implicated in other conditions - in particular some forms of dementia - so it may prove to play a contributory role in a wider number of neurodegenerative diseases. (For further information on TDP-43 and its role in this programme please see the background briefing paper.)

The skin cells are initially 'reprogrammed' to generate induced pluripotent stem cells (iPS cells) which are very similar to stem cells derived from human embryos. The iPS cells can then be induced to turn into either of the two main cell types known to be involved in the disease: the motor neurons which degenerate in MND; and other vital support cells called astrocytes.

Although it is the motor neurons that die in MND, it is known that the disease is not solely restricted to these cells. The support cells that normally play a role in nurturing motor neurons can inadvertently cause damage, and it is through this mechanism that scientists believe that the disease spreads from one part of the brain and spine to the next.

The MND Association's programme will address a fundamental question of whether the support cells from healthy or TDP-43 mutant gene carrying patients are injurious or protective to motor neurons. In addition, experiments growing motor neurons and support cells from different donors in the same dish (a process called 'co-culture') will address whether this disease spread seen in the human condition can be reproduced in the laboratory.

The programme has three components:

• Stage 1: Create high-yield, high quality populations of motor neurons and support cells from skin cells
• Stage 2: Establish a laboratory model of motor neurons and support cells, to characterise their behaviour in physiological (normal) conditions and under conditions of cell stress
• Stage 3: Examine how genes are switched on and off within the cells, in an attempt to identify 'gene expression signatures' associated with motor neuron disease.

Prof Siddharthan Chandran from the Euan MacDonald Centre for MND Research at the University of Edinburgh; Prof Sir Ian Wilmut at the Medial Research Council Centre for Regenerative Medicine at the University of Edinburgh; Prof Christopher Shaw at the Institute of Psychiatry, King's College London; and Prof Tom Maniatis of Columbia University New York will all be working on various components of this three stage programme. (For further information on the three-stage programme please see the background briefing paper.)

Prof Siddharthan Chandran, the programme's principal investigator, will be working with Prof Sir Ian Wilmut to refine and optimise the reprogramming procedure to ensure as many healthy cells as possible can be generated.

He says: "Bringing together the genetic revolution of the last decade with the spectacular progress in stem cell research means we can now model human disease in a dish."

Prof Sir Ian Wilmut adds: "This funding from the MND Association will help us to understand why specific nerves die in motor neuron disease. This is a critical next step towards the ultimate goal of developing an effective treatment."

The studies to examine the general health and structure of the different cell types when interacting with each other will be carried out at the University of Edinburgh and also by leading MND researcher Prof Christopher Shaw. Prof Tom Maniatis will work on the third stage of the programme by identifying 'gene expression signatures' associated with the disease.

Dr Brian Dickie concludes: "This is a highly promising field of research to help increase our understanding of this disease. The outcomes from our programme will have a powerful impact in shaping the future of motor neuron disease research and enhancing future international research collaboration. Only by working together across the globe will we achieve our goal of truly defeating motor neuron disease."

Source: University of Edinburgh