Our First Strategic Priority for MND Research in Focus: Validating Therapeutic Targets

In April, we launched our Research Strategy, Catalysing a Cure, outlining our continued commitment to fund, guide and enable the smartest, most efficient research to expedite the development of new treatments for MND.Our strategy sets out three strategic priorities for the next five years:

• Validating Therapeutic Targets
• Accelerating New Treatments
• Improving Translation

But what do these terms really mean? We’re publishing an article on each strategic priority, starting with Validating Therapeutic Targets, to help you understand exactly how investing in these areas will bring us closer to a world free of MND.

What is a therapeutic target?

A target is a protein, gene or system in the body that can be acted on by a treatment, to change the course of a disease. People living with diabetes take insulin, which acts on the insulin receptor to regulate glucose levels in the blood. In this example, the insulin receptor is a therapeutic target - it can be acted on to change the state of the disease.

Tofersen, the latest drug to be approved for the treatment of MND in the US, binds to and silences the mRNA of the faulty SOD1 protein that is present in the motor neurons of people living with MND who carry a SOD1 mutation - approximately 2% of all MND cases. Here, SOD1 mRNA is the therapeutic target. Find out more about how cells make mRNA from our infographics below.

How are therapeutic targets validated?

Validating a new target is a crucial first step in the drug development process; it’s what gives researchers the evidence they need to show that a particular therapeutic strategy could be worth pursuing. Before tofersen was developed, researchers had to prove that acting on, or altering SOD1 mRNA in some way, could provide therapeutic benefit while ensuring it was safe to use and caused few unwanted side effects. Only then would the time and money be invested into developing the new treatment.

To robustly validate new targets, researchers ask questions such as:

• “Is the target linked in some way to MND?” and “Is the target present in the right cells e.g. the motor neurons?”. These questions are answered using tissue samples and genomic data from people living with MND.
• “Does modulating the target alter the disease course?”. This is done in cell and animal models using specialised techniques that can increase or decrease the amount of the target in the model. In cells, researchers might look for increased survival of motor neurons and in animals, they might look for a slowing or stopping of disease progression.
• “Is the target ‘druggable’?”. Researchers study the physical characteristics of the target and the route that the drug would need to take to reach it, in order to assess whether the drug could realistically modulate the target’s activity.

New targets for MND

As our understanding of the biology of MND continues to grow, so too does the list of potential proteins, genes or systems in the body that are under investigation as potential therapeutic targets. There is increasing evidence that several biological systems could be involved in MND development and/or progression (highlighted in the image below), and these are now being explored to reveal potential targets for future treatments. Before these targets can be taken forward to develop new treatments, in-depth research is required to “validate” their potential.

Research to validate therapeutic targets is expensive and complex, requiring a lot of expertise. Traditionally, more funding has been available to identify potential new targets than to carry out dedicated validation studies, particularly to the high standard of those carried out by industry experts, such as pharmaceutical companies. This is why we're making target validation a strategic priority of our new research strategy.

Over the coming years, we will invest in and support researchers to robustly validate new targets, so that either:

• Validated targets can be prioritised for drug development, or
• Research on targets that can’t be validated is stopped, avoiding waste of time and money

We will prioritise targets that are related to mechanisms that underpin most cases of MND, so that treatments are likely to benefit the majority of people with the disease too, because we recognise that people living with MND do not have time to wait. We will explore innovative ways to accelerate progress in this area, catalysing the discovery and development of new treatments.