Hunting for injured nerves: Discovering diagnostic and therapeutic biomarkers for painful nerve injury using targeted binding domain libraries from the shark immune system
Lead supervisor: Dr Alexander Davies
Co-supervisor: Associate Prof. Simon Rinaldi
Commercial partner: Elasmogen Limited
Chronic pain as a result of nerve damage or disease – known as neuropathic pain - affects as many as 7-10% of the population in the UK in their lifetime. With the healthcare and societal cost estimated to be £billions every year, and current treatments for neuropathic pain either inadequate or resulting in serious side-effects, new approaches to diagnosis and treatment are urgently required.
The immune response to peripheral nerve injury has long been thought to play a key role in the potential development as well as resolution of neuropathic pain. Yet immune targets have been overlooked as a point of therapeutic intervention.
We have previously shown that injured sensory nerves become a target for the immune receptors that signal to circulating natural killer (NK) cells, resulting in the pruning of damaged sensory nerve fibres that are otherwise a significant risk factor in neuropathic pain (Davies, 2019, Cell; Kim, 2023, Pain). More recently, our cell-based profiling approach suggests that a host of activating and inhibitory lymphocyte receptors interact with ligands endogenous to the peripheral nervous system that importantly appear to be regulated by axonal injury.
The presence of inducible proteins at the extracellular surface of injured nerves provides a unique opportunity to achieve two key objectives for the diagnosis and treatment of neuropathic pain:
1) diagnose the presence of pathological sensory nerves in a live organism in real time.
2) develop a targeted immune-based therapy for the treatment of neuropathic pain.
To achieve these goals the Davies’ lab has teamed up with Dr Obinna Ubah at Elasmogen to leverage their soloMER technology platform to screen for novel binding interactions targeting domains specific to neuropathic disease. Using Elasmogen’s proprietary discovery pipeline, we will develop a ligand-binding screening programme to create a library of high-affinity, highly selective nanobodies capable of recognising injury-induced proteins on murine and human sensory neurons. Candidate molecules will be validated in heterologous expression systems and primary murine cell cultures using live cell imaging, as well as human induced pluripotent stem cell (iPSC)-derived sensory neurons with axonal injury induced by laser ablation. Candidate nanobodies will be taken forward in mouse models of peripheral injury and neuropathy, to identify target binding in vivo using fluorescence and radiolabelled conjugation.
The outcome will be a set of molecular tools to sensitively and selectively detect downstream events of peripheral nerve injury. Therapeutic targeting of injured axons will subsequently be modelled in proof-of-concept experiments using murine and human multi-cellular neuro-immune co-culture platforms developed in the Davies lab. This dual species approach will ensure that any findings are well-placed to achieve rapid to clinical translation.
This interdisciplinary project extends the remit of Elasmogen’s technology beyond autoimmune and inflammatory disease to the neuro-immune space, with potential applicability to wider neurological conditions with immune involvement. The collaboration will also mark the Davies’ lab’s first foray into clinical technology development, and facilitate key knowledge exchange in state-of-the-art neuro-immune cell culture platforms and biologic drugs discovery tools with the explicit aim of research translation into novel therapeutics for neuropathic pain.
Apply using course: DPhil in Clinical Neurosciences
