A breakthrough in a stem-cell programme funded by the UK-based MND Association has greatly improved the chances of developing effective treatments for Motor Neurone Disease (MND) of which the predominant form is Amyotrophic Lateral Sclerosis (ALS).

An international team led by the UK’s University of Edinburgh and King’s College London, and Columbia University in New York, has for the first time made living human motor neurones that feature key properties of MND/ALS. They made the diseased nerve cells using stem cells derived from adult skin.

Having such a laboratory model of a disease to hand vastly improves the speed with which potential new drugs can be screened, and helps expand understanding of the disease.

Programme leader Dr Siddharthan Chandran, Professor of Neurology at the University of Edinburgh, and colleagues, write about this key milestone in the 26 March online, ahead of print, issue of PNAS.

Chandran said in a statement:

“Using patient stem cells to model MND in a dish offers untold possibilities for how we study the cause of this terrible disease as well as accelerating drug discovery by providing a cost effective way to test many thousands of potential treatments.”

Motor Neuron Disease (MND) is a term that covers several different conditions distinguished by the premature degeneration of motor nerves (called neurones or neurons).

As the disease progresses, it causes weakness and wasting of muscles, leading to gradual loss of mobility in arms and legs, and difficulties with speech, swallowing and breathing.

There are four main types of MND, each affecting people in different ways. The most common form is ALS, which is characterised by weakness and wasting in the limbs.

Average life expectancy for ALS is from two to five years from onset of symptoms, although there are rare examples of people with ALS living much longer than this, perhaps the most famous being the 70-year-old British theoretical physicist Stephen Hawking who was diagnosed in his early 20s.

A rare, inherited form of MND is caused by a mutation in the TDP-43 gene (the mutation is known as M337V). Although the mutation itself is rare, the protein that the gene codes for plays a key role in the majority of MND cases.

For their study, Chandran and colleagues took skin cells from a 56-year male donor with the rare form of the TDP-43 gene, and using a cocktail of chemicals, “reprogrammed” them to become first stem cells (induced pluripotent stem cells or iPSCs, not unlike the ones derived from embryos), and then motor neurones.

The motor neurones with the abnormal TDP-43 were different to motor neurones made from skin cells of healthy people in several distinct and important features. For instance, they did not live as long and they were more vulnerable to damage.

The researchers also found that the protein from the faulty TDP-43 gene had a greater tendency to aggregrate and form clumps. This “misaccumulation” is a hallmark of diseased neurones in MND and offers scientists the first ever opportunity to observe directly the effect of abnormal TDP-43 on living human cells.

In a statement, the MND Association, describes the study as “proof of principle” that skin cells can be successfully converted into diseased motor neurones and a significant milestone in the £800,000 programme, whose aim is to produce a robust human cell model of MND that faithfully reflects the cellular events happening in the patient, and can be used by scientists around the world.

Dr Brian Dickie, director of research development at the MND Association, said the achievement was also “testament to the importance of international collaboration, with eminent scientists from leading institutions around the world focused on the common goal of understanding and, ultimately, defeating this devastating disease”.

Written by Catharine Paddock PhD