Safety, efficacy and mechanism of action of non-paralytic botulinum toxin molecules for the treatment of trigeminal neuralgia and other facial pain conditions

Scientific basis and translational aspects:
Trigeminal neuralgia (TN), and other facial pain disorders, are characterised by chronic, severe and extremely disabling facial pain. Pharmacological treatments are limited and often lack efficacy, while have severe side-effects. The use of botulinum toxin A, e.g. botox, has shown potential in off-label clinical trial, however its analgesic effects are limited by the toxins’ paralytic effect. To overcome this limitation, our lab utilises bioengineered recombinant botulinum toxins (BITOX) with abolished paralytic function while maintaining their analgesic potential, with the aim to identify a candidate molecule that will enter a first-in-human trial.
Techniques and skills:
The PhD student will develop a breath of in-vitro, in-vivo and analytic skills, and conceptual transferable skills including:
Molecular biology and protein engineering, which include techniques in recombinant DNA technology and protein expression. In-vitro cellular and functional assays to test activity on neuronal cells, viability and toxicity assays. Establishment and handling of animal models of facial pain, behavioural pain assessments and monitoring of potential paralysis. Imaging techniques will study sites of action within tissue, RNA sequencing of neural tissue and biostatistics will identify differentially expressed genes and biological pathways. Interdisciplinary collaboration and communication skills, working along clinicians and patients.
Overarching aims of the project:
This translational research programme aims to:
A. Investigate the in-vivo effects and safety of BITOX in preclinical models of facial pain. Our pilot data already show non-paralytic and analgesic properties following treatment with a single dose.
B. To investigate the mechanism of action of BITOX proteins by examining their biodistribution in the peripheral and central nervous systems, and RNA changes in neural tissue.
Objectives for each year:
• Year 1 will engage in in-vivo cellular and functional assays to test cell viability, and BITOX activity on neurotransmission. This work will further prepare necessary stock concentrations for future study. In parallel, initial work with the patient charity (Trigeminal Neuralgia Association) will address the feasibility of a survey amongst its patient database on the botox injection protocols utilised in TN patients.
• Year 2 will test and compare the effectiveness, longevity, therapeutic window and safety of BITOX molecules in neuropathic and inflammatory pain models. This work will build the basis for the in-vivo efficacy and toxicology studies that are needed towards the first-in-human trial.
• Year 3 will examine the mechanism and sites of action of BITOX in neural tissue. RNA sequencing will be used to examine changes in gene expression in the trigeminal ganglia following treatment.
• Year 4 will focus on biostatistics on the RNA seq data and the genes’ biological pathways and functional analysis.
• 3-month rotation project: GDPR-compliant patient survey in collaboration with our charity partner to examine the injections protocols and dosage of botox used in TN patients, and global impression of change. This will inform the injections protocol for the first-in-human trial with BITOX proteins.