A simple facial movement—speaking, chewing, or even a light breeze—can trigger a bolt of electric-shock pain so severe that trigeminal neuralgia is known as the “suicide disease.” Up to 0.8% of people suffer from it, and 40% endure more than ten attacks per day. Existing drugs fail in half of patients due to side effects or loss of efficacy, and surgery carries a 30% relapse rate. The problem is rooted in overactive trigeminal nerve cells, where a potassium channel called Kir4.1 has lost its ability to calm them down. This project will use AstraZeneca’s automated high-throughput screening to test hundreds of thousands of small molecules for compounds that switch Kir4.1 back on. If successful, the result would be an affordable pill that restores the nerve’s natural braking system, replacing expensive, invasive treatments with a widely accessible drug. That could shift the standard of care from palliative management to targeted therapy, reducing both patient suffering and the estimated $100 million annual cost of TN surgery in the US alone.
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Trigeminal neuralgia (TN) is a debilitating condition characterised by severe sudden, electric shock-like facial pain triggered by everyday actions such as speaking, drinking, or chewing. Epidemiological studies have linked TN to an increased likelihood of anxiety, depression and risk of suicide, in fact the pain is so severe, TN is colloquially known as the “suicide disease”. TN impacts a relatively high proportion of the population (0.1 – 0.8%), and has increased prevalence in women (F:M ratio 3:2). Incidence increases with age, reaching 20 per 100,000 over 60 years old and this also coincides with increased frequency and severity of attacks, further impairing life quality. 40% of patients experience greater than 10 attacks per day with some suffering several hundred. Attacks last from tens of seconds to a few minutes, with some patients also experiencing continual pain. Following onset, trigeminal neuralgia is rarely, if ever cured and sufferers mainly undergo palliative pain management. Such front line treatments currently include the antiepileptic drugs carbamazepine and oxcarbazepine which offers initial pain management, but due to loss of efficacy and adverse effects such as dizziness and nausea, these drugs are withdrawn in 50% of patients. Those that do not respond to medication require specialist neurologist care which can be expensive and difficult to access. Pharmaco-resistant patients are commonly subjected to more invasive treatments such as nerve blocks or surgery to relieve the trigeminal nerve pressure caused by nearby blood vessels. Surgery involves greater risks such as parathesis (numbness) and up to 30% of patients experience relapse of severe pain following surgery. The high incidence rate and cost of treatment for medications, specialist consultations, imaging and invasive interventions place a huge burden on healthcare systems, and TN surgery alone is estimated to cost ~$100M annually in the US. According to 360iResearch the current TN therapeutics market is valued at $262.17M and is expected to rise to $416.90M by 2030. Trigeminal neuralgia is caused by abnormal overactivity of the trigeminal nerve, which controls sensation in the face. In about 75% of cases, this is due to pressure from nearby blood vessels. The rest are linked to other neurological conditions like multiple sclerosis or have no known cause. Recent research shows that nerve hyperactivity disorders—such as trigeminal pain, epilepsy, and migraine—often involve weakened inhibitory control in the nervous system. One key factor is disrupted potassium (K?) balance, particularly from reduced activity of the Kir4.1 potassium channel. Restoring Kir4.1 function through gene therapy has shown pain relief in animal models. However, gene therapy is expensive and not widely accessible. To overcome this, we aim to develop affordable small-molecule drugs that activate Kir4.1 and offer a new treatment for trigeminal neuralgia. At UCL, we have established a K+ conductance assay which is applicable to drug discovery. However, at our current medium-throughput capacity, screening a large library of novel drugs will be time consuming and inefficient. Working with AstraZeneca and their automated high-throughput screening capabilities, we will upscale our assay to find a novel analgesic for trigeminal neuralgia. Small molecules still remain the best option for wide-spread accessibility with low-upscaling costs. Therefore discovering a novel analgesic using the AstraZeneca small molecule library has the potential to benefit those who suffer from trigeminal neuralgia globally.
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