Martina Slapkova – Research Information Co-ordinator at the Motor Neurone Disease Association

Motor neuron disease (MND), also known as Amyotrophic Lateral Sclerosis across the globe, has been puzzling researchers and clinicians ever since it was first characterised by the French neurologist Jean-Martin Charcot almost 150 years ago. An estimate of 5,000 people live with MND in the UK at any one time, with one’s lifetime risk being 1 in 300.

Initially manifesting itself by weakness in voluntary muscles that control limbs and speech, the disease gradually takes over the whole body, leaving the person trapped in a failing body – unable to move, talk, or eat. Death usually occurs 2-3 years after diagnosis, often due to respiratory failure. There is no cure.

These devastating symptoms are caused by diseased motor neurons, which over time become unable to communicate with the muscles. Although we are still in the stages of identifying what exactly happens in the body to make the neurons go awry, substantial progress has been made in the past few years, making us hopeful of a new treatment.

Where are we now?

Clinical trials have been relentlessly testing drug targets ever since the first ever MND drug, riluzole, was licensed in the UK in 1996. However, although considered a standard treatment for anyone diagnosed with MND, riluzole only prolongs survival by around 3 months.

Fast forward two decades when a second drug, edaravone, was licensed in Japan, South Korea, USA and Canada. Originally, edaravone was developed as an intravenous treatment for acute ischemic stroke. When it was later tested in rodent models and subsequently in people with MND, reduction of oxidative stress was observed. Follow-up trials were however only able to identify modest effect in a small subgroup of patients whose symptom progression was moderately slower. To this date, data on survival are still sought.

Where do we go from here?

With only two drugs under our belt, and no effective treatment, the MND research community is far from losing hope and we are looking ahead of exciting times. There are many avenues researchers are exploring, each targeting a different mechanism by which the disease is suspected to develop and progress. Although the precise cause of why motor neurons die isn’t known, many pathogenic processes have been proposed.

One common overarching pathological hallmark of the disease is the accumulation of sticky clumps of aggregated proteins in the affected cells. One such protein, found aggregated in almost all cases of MND, is called TDP-43. Accumulation of this protein outside its normal location in the nucleus creates toxic aggregates, slowly taking over the control centre of the neuron. An investigative drug arimoclomol stimulates production of natural chaperones – heat-shock proteins – which prevents potentially toxic proteins from being able to aggregate and clump. Its positive safety profile and ability to cross the blood-brain barrier makes it a good drug candidate, and it is now being tested for its effectiveness across the world, including the UK.

Post mortem studies of brain and spinal cord tissue also revealed changes attributed to the effects of free radical damage, making oxidative stress another possible disease mechanism. A new investigational drug, Copper ATSM, is now being tested to investigate its effectiveness to selectively deliver copper to hypoxic cells, which has already been successful in cell and animal models, and recently found safe to administer in humans.

Another suggested mechanism involves mitochondria, whose dysfunction is thought to induce abnormal levels of energy production. Cell and animal models are now focusing on improving antioxidant defences to improve mitochondrial function and gene editing to regulate mitochondrial permeability.

It is not however only about the neurons. The support cells of neurons, glia, normally have a protective and nurturing role in the central nervous system, however, in MND, they can cause more damage than good. Two specific types of glial cells, astrocytes and microglia, have the ability to turn to the ‘dark side’ and produce toxic environment to the motor neurons. This results in an inflammatory response where even the healthy motor neurons are attacked. Therapies such as low-dose interleukin-2, currently tested in a clinical trial MIROCALS, are now focusing on increasing the amount of regulatory T-cells (Treg) to help fight the inflammation. Higher amounts of Treg cells, which are thought to calm microglia, are found in MND patients with slower disease progression, hinting at a potential mechanism.

The role of genes

MND is a disease of a complex origin, and a combination of genetic, environmental and lifestyle factors is necessary for the disease to develop. And although some involvement of genes is suspected in the majority of MND cases, a subgroup of ~10% of patients has a specific proneness to the disease due to an inherited genetic mistake.

Although a heterogenous disease, clinical manifestations of MND are similar across patients regardless of the cause. Therefore, having a number of genes identified to be associated with the disease provides the advantage of focusing treatment efforts into fixing these mistakes first.

One way to do this, which is already being trialled for one of the most common genes associated with MND – SOD1 – is by using antisense therapy, whose recent success in other diseases, including treating Spinal Muscular Atrophy, gives it a strong foundation. This therapy allows a synthetic strand of RNA to bind to the gene’s messenger RNA, preventing the faulty protein from being made (effectively turning the faulty gene off). Interim findings have showed decrease in SOD1 protein in the CSF of people with MND and a trend towards reduced clinical decline. Another gene, C9orf72, which is also implicated in frontotemporal dementia, a disease sometimes co-occurring with MND, is another target of an antisense trial.

Can a virus be to blame?

The theory that MND might be of viral origin has been around for some time and has recently resurfaced with the proposition that the human endogenous retrovirus-K (HERV-K) might be linked with the disease. These ancient viruses often go unnoticed in our bodies until they get activated from their dormant state. Post mortem studies of people with MND revealed presence of proteins made by the retrovirus that were found to be toxic to motor neurons and triggering neurodegeneration. Although the reason why this happens isn’t yet fully understood, antiretroviral therapies currently used for the treatment of HIV/AIDS are now being tested to suppress the activity of HERV-K to explore its efficacy in MND.

The journey is long, but the target is getting closer

Researchers have made a great progress over the past few decades and with the recent boom of new technology, including whole genome sequencing, induced pluripotent stem cell modelling and gene therapy, our community is hopeful and motivated than ever to tackle MND, by attacking it from every possible angle.

The MND Association is relentless in its fight against the disease and by funding research into the causes, treatments, symptom management and quality of life, while supporting the care needs of people living with MND and their carers, we hope for a world free of MND.