A research paper published recently has investigated the effect of a compound called ‘NU-9’ in mice models of MND.
Before we go on, it is important to define ‘compound’ in this context. A compound is something that has pharmacological or biological activity that is likely to be therapeutically useful. It serves as a starting point for chemical modifications to improve its effectiveness and may be developed into a drug that targets a specific mechanism of disease. NU-9 was initially identified based on its ability to reduce the clumps of faulty SOD1 protein that builds up in motor neurons – a hallmark of MND.
The team of Dr Hande Ozdinler, from Northwestern University in the USA, in collaboration with Dr Richard Silverman, found that NU-9 appears to have an effect on the upper motor neurons (UMNs) of mice that have mutations in the SOD1 and TDP-43 genes, which are associated with MND in people.
Upper motor neurons and lower motor neurons
UMNs have a unique role in collecting and transmitting information from the brain to the lower motor neurons (LMNs) in the spinal cord. These ‘messages’ are then passed to the muscles, causing them to move voluntarily. One of the characteristics of MND is the degeneration of UMNs over time, so improving the health of these is now considered a necessity.
In MND, the upper motor neurons, which are in the brain, and the lower motor neurons, which are in the spinal cord and brainstem, may be affected at the same time.
Upper motor neuron degeneration generally causes spasticity (muscle tightness), slowness of movement, poor balance and incoordination, while lower motor neuron degeneration causes muscle weakness, muscle atrophy (shrinkage of muscles) and twitching (fasciculations). These can occur in combination in MND, as upper and lower motor neurons may be affected.
What did the study look at?
In this study two mice models were used – SOD1 and TDP-43 – which show some symptoms of MND. These models were chosen as the UMNs in mice share many similarities with human UMNs.
The mice were split into two groups, with one group being given NU-9 through their food and the other remaining untreated. All the mice then underwent a series of locomotion tests which assessed their ability to hang on to a wire mesh (hanging wire test) and balance on a rolling surface (rotor-rod test). Post-mortem tissue was also examined. As UMNs and LMNs are affected in MND, the researchers looked at the effect of NU-9 on both of these.
What did the results show?
By examining post-mortem tissue under a microscope, it was seen that mice who had been fed NU-9 had more UMNs than the untreated group. However, LMNs were lost at the same rate in the two groups.
In the locomotion tests, the treated animals performed better in the wire hanging test, which is thought to be a measure of UMNs, with there being no difference between the groups in the rotor-rod test – thought to be a measure of LMNs.
What does this mean and how will it affect people living with MND?
Although this work is still in the pre-clinical stages in animals, the results suggest that NU-9 may have a targeted effect on UMNs. The authors state that previous clinical trials have not focused specifically on UMNs and most have looked for effects in both UMNs and LMNs. However, as these are different types of cells with different origins and roles, they should be considered separately as potential therapies may affect each differently.
There are different forms of motor neurone disease that affect UMNs, LMNs, or both so, if NU-9 eventually becomes a treatment, it will not be suitable for everyone with MND.
Amyotrophic lateral sclerosis (ALS) is the most common type of MND. It affects both upper and lower motor neurons, leading to limb muscle wasting and difficulties with speech and swallowing. Life expectancy is 2-5 years from symptom onset.
Progressive bulbar palsy (PBP) affects both the upper and lower motor neurons and begins by affecting the muscles that control speech and swallowing. Limb muscles may be affected later. Life expectancy is six months-3 years from symptom onset.
Primary lateral sclerosis (PLS) is a rare form of MND that affects the upper motor neurons only. Weakness and stiffness usually begin in the lower limbs but may later affect speech and swallowing. It is very slow progressing and is not usually life-shortening.
Progressive muscular atrophy (PMA) affects the lower motor neurons only. Symptoms may begin with clumsiness in the hands with generalised muscle wasting and weakness. Life expectancy is usually more than five years.
Next steps
This work looked at two different animal models – SOD1 and TDP-43 – reflecting different forms of MND. It found that NU-9 had an effect on UMNs only. Much more work is needed to further assess the effectiveness of NU-9 on UMNs in people through rigorous and thorough clinical trials, and we look forward to seeing where this early research will lead.
Resources
Read the full paper: Improving mitochondria and ER stability helps to eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology
Another very very interesting research report for me as nearly 7yrs since formally diagnosed