Science
At NMD Pharma we are focusing on novel treatments for neuromuscular diseases. Neuromuscular diseases involve impairment of the motor system, including the motor neurons and the skeletal muscles that they control (see figure 1). The motor neurons are akin to the wiring which carries signals from the brain to peripheral muscles, and the muscles are the motors responsible for movement. The motor system controls movements of arms and legs to perform everyday tasks varying from walking, riding a bicycle, and brushing one’s hair to controlling one’s posture and performing vital functions such as breathing.
The motor system that controls movement consists of the motor neurons and the muscles which they innervate
(figure 1)
In order to accomplish such tasks, motor neurons contact the muscle in a specialized region called the neuromuscular junction (see figure 2). At this junction, also known as a synapse, a chemical signal (acetylcholine) is released by the electrical signal in the terminal end of the motor neuron. Once released it binds to specific acetylcholine receptors on the muscle fibre surface in the region of the neuromuscular junction. The receptors are activated by acetylcholine leading to influx of positively charged ions into the muscle fibre in the region of the neuromuscular junction and this creates a local change in the membrane potential i.e. a synaptic potential. This synaptic potential can in turn trigger a regenerative and propagating electrical signal in the muscle fibre provided that the synaptic potential is large enough. This propagating signal triggered at the neuromuscular junction travels along the length of the muscle fibre and into the transverse t-tubular system. When the interior of the muscle receives this electrical signal, it activates the release of calcium (Ca2+) from an intracellular depot, and the Ca2+ signal then triggers activation the muscle motor proteins resulting in muscle shortening and force production.
The specialized region of the muscle where the motor neuron communicates the activation signal is at the neuromuscular junction. This is a specialized synapse between a nerve and muscle. In neuromuscular diseases there are deficits in both the motor neuron side (pre-synaptic) and on the muscle side (post-synaptic)
(figure 2)
In certain diseases, there are disruptions of the normal signal at the neuromuscular junction because synaptic potentials at the neuromuscular junction are too small. This occurs in diseases such as myasthenia gravis (MG) and spinal muscular atrophy (SMA) where there is a loss of motor neurons and reduced signals coming into the neuromuscular junction. Scientists at NMD Pharma have discovered that inhibiting the flow of negatively charged Cl-ions across the membrane can rescue the deficit on the muscle side of the junction and hope that this can overcome deficits in diseases such as MG and SMA.
At NMD Pharma we are using a novel approach to treat neuromuscular disorders by enhancing muscle force production and motor function with selective inhibitors of the ClC-1 chloride ion channel. A novel platform technology has been developed to support the identification of these new ClC-1 inhibitors. This platform includes a streamlined sequence of biological assays that help to identify novel and potent ClC-1 inhibitors in isolated muscle fibres, in intact native skeletal muscle, and which show promise in in vivo muscle in both healthy animals and in animal models that mimic human diseases. In our planed human studies, the biological marker (biomarker) of electrical signals in skeletal muscle will be used to evaluate the benefit of our ClC-1 inhibitors. The translation from preclinical to human disease conditions is enhanced by this ability to assess the underlying electrical signal in muscle and to help us understand how this improves muscle function in neuromuscular diseases. The novel and exciting platform technology will be utilized to identify new treatments for devastating diseases of the human motor system, such as MG and SMA.
