Peripheral Neuropathy and Our Drug

What Is Peripheral Neuropathy?

The human nervous system has two main parts: the central nervous system, or CNS, made up of the spinal cord and brain, and the peripheral nervous system, consisting of all the nerves outside the CNS. The peripheral nervous system includes sensory neurons, the longest cell type in our body. Sensory neurons pick up signals from sensory receptors at the dendrites and release them at their axon terminals to transfer them to the next neuron or the spinal cord and, ultimately, the brain. Normally, all of this occurs virtually instantaneously.

In peripheral neuropathy (PN), the peripheral sensory nerves become damaged as a result of injury or disease. In diabetic peripheral neuropathy (DPN), for instance, the degeneration of nerve terminals occurs systemically but is observed in the outermost limbs, including the hands and feet of patients. Eventually, the disease progresses systemically to affect the eyes, heart and kidneys of the patient. It is believed to be caused by a high blood glucose level that disrupts the neurotransmission. This nerve damage leads to a disturbance in sensory function and symptoms ranging from tingling or persistent pain to a muted or complete loss of feeling.


Our Solution

While peripheral neuropathies can be initiated by diverse events (diabetes, HIV, chemotherapy, etc.), it is believed that most display some degree of mitochondrial dysfunction. Disruption to normal mitochondrial activity results in a chronic axonal energy deficit that is the proximate cause of the damage to peripheral nerves, one of the highest users of cellular energy, and subsequently to the symptoms of neuropathy.  

Our team discovered this dysfunction can be disrupted and normal cell function (homeostasis) can be reestablished through inhibition of a GPCR (G-protein coupled receptor) found on the membranes of axon terminals of peripheral nerves. This inhibition can occur through the introduction of antagonists to this GPCR system. Homeostasis in sensory neurons stimulates nerve growth and proper functioning through the formation of new neural connections between damaged and undamaged neurons, i.e., plasticity.

The Drug’s Mechanism

WST-057 is a topical reformulation of one of these antagonists. This antagonist is the active ingredient in WST-057, and a specific GPCR antagonist that has been in use in Asia and Europe for nearly 40 years in an oral (systemic) pill to treat peptic ulcers. It was selected by our team because of its historical systemic safety (ingested) in large populations for decades. WST-057 takes this same active ingredient which is applied topically once a day to the skin to treat the nerve damage locally. This localizes the active ingredient to target the GPCR receptors found on the ends of the peripheral nerves found in the extremities of patients. Binding the receptor activates a cascade of protein, including AMP-activated protein kinase (AMPK), that then drives mitochondrial function. The new proteins increase the activity and/or number of mitochondria which leads to an increase of available ATP (energy).

The ATP molecules provide the energy necessary for nerve growth. The nerve growth can be seen in two ways: the extension in axon length and the formation of new axons in a process known as branching (shown below).