Neuromuscular diseases

 

Skeletal muscles represent around 40% of the body and their contractions enable movement including essential human behaviour such as breathing, eating, walking, and speaking. They are composed of long muscle fibre cells that extend from tendon to tendon, and they can be several centimetres long. The activity of muscle is controlled by the nervous system and each muscle fibre receives input from the nervous system at a small area of the muscle fibre. This specialized membrane area is known as the neuromuscular junction.

Intention to move is initiated by the generation of electrical signals in the brain that travel from the brain through both an upper and a lower motor neuron before arriving at the neuromuscular junction. At this junction, electrical signal in motor neurons must be transmitted to similar electrical signals in the muscle fibes via a process known as neuromuscular transmission. The resulting electrical signals in the muscle fibres travel along the muscle fibres length to trigger an elevation in Ca2+ in the muscle that in turn triggers force production by contractile proteins.

Neuromuscular diseases represent a broad range of disease characterized by muscle weakness and excessive fatigue. Muscle weakness and fatigue can arise at any of the steps in the activation of muscle fibres. The neuromuscular junction is known to be involved in multiple neuromuscular disorders and compromised transmission at the neuromuscular junction underlies failing muscle fibre activation in several diseases.

Neuromuscular_junction.png

 

Some neuromuscular diseases have a genetic basis, others are acquired during a person’s lifetime with no identified genetic cause. Examples of conditions which affect the motor neuron or the neuromuscular junction include spinal muscular atrophy (SMA), Charcot Marie Tooth Disease (CMT) and motor neuron disease (MND or ALS). An example of a disease specifically affecting the neuromuscular junction is myasthenia gravis (MG), and diseases that predominantly affect muscle include the muscular dystrophies such as Duchenne and Becker muscular dystrophy.

NMD Pharma is developing novel approaches to improve activation of muscle fibres at the neuromuscular junction. This approach is currently being developed for myasthenia gravis and spinal muscular atrophy.

Pre-Post-Synaptic-Dysfunction-with-cmpd_1.png
Pre-Post-Synaptic-Dysfunction-with-cmpd_2.png

Myasthenia gravis

Myasthenia gravis (MG) arises during adulthood as a result of an autoimmune reaction, that is to say the body makes antibodies to its own proteins - in most MG cases against the acetylcholine receptor on the surface of the muscle. The antibodies cause loss of this receptor from the muscle and a gradual destruction of muscle fibres in the neuromuscular junction of the muscle fibres. This results in failure of signals transmission from motor neurons to muscle fibres at the neuromuscular junction, and therefore failure to activate muscle contractions. Patients notice fluctuating weakness and tiredness, particularly towards the end of the day. Eyes are often affected with drooping eyelids or double vision, as well as more generalised weakness affecting a person’s ability to perform routine activities of daily life. As with other autoimmune diseases, women are more prone to MG compared to men. Because of its fluctuating nature, it can be difficult to diagnose in some people, leading to lengthy delays in receiving treatment. Diagnosis is often made on the basis of a history of fluctuating muscle weakness, a blood test for the antibody, and sometimes nerve stimulation tests (electrophysiology) in hospital.

Spinal muscular atrophy

Spinal muscular atrophy is a genetic condition resulting in loss of smn protein which is essential for the normal development and function of multiple tissues including neurons. It exists in 4 main types, based mainly on age of onset and degree of disability. Type 1 SMA develops in babies less than 6 months of age and is severe and life-threatening. Type 2 develops in the first 18 months of life and is debilitating in terms of development and mobility, but modern treatments have improved the outlook for these children. Nonetheless residual symptoms persist through life and are a suitable target for treatment. Similarly Type 3 SMA usually appears after 18 months and persists into adulthood. Some patients are ambulatory (usually with aids), others require a wheelchair to get about. All forms of the condition could potentially benefit from a therapy that enhances neuromuscular transmission, which has been shown to be impaired in SMA.