Development of peripheral nerve specific biomarker assays: from in vitro neuropathy models to clinical validation

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Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are conditions where the immune system, the body's natural defence against illness and infections, mistakenly attacks the nerves. This can cause progressive paralysis and, in severe cases, people can lose their ability to walk, swallow and breathe. About 1 in 20 people with GBS die, and many are left with long-term disability. CIDP patients often require several years of treatment with immunosuppressant medicines to 'damp down' the immune system and reduce inflammation. Alternatively, they receive regular infusions of intravenous immunoglobulin (IVIG), a costly and scarcely available treatment made from donated blood, given to help stop the harmful antibodies damaging the nerves. A plasma exchange, also called plasmapheresis, is sometimes used instead of IVIG and involves being attached to a machine that removes blood from a vein, filters out the harmful antibodies, and returns the blood to the body.Treatments for these diseases are only partially effective. Part of the problem is that we do not have biomarkers (naturally occurring molecules) to diagnose and assess response to therapies, as the amounts released by the damaged nerves are tiny and extremely difficult to measure. Recently, very powerful machines called "single molecule analysers" (SiMoA) have enabled us to measure biomarkers at 100-2000 times lower concentrations than before (equivalent to being able to detect a teaspoon of sugar dissolved in a full-sized Olympic swimming pool).In my project, I will study two potential biomarkers of nerve damage, peripherin and periaxin, and develop SiMoA assays to measure them in the blood. I will grow human peripheral nerve cells in a dish in the laboratory using stem cells, which have a special ability to turn into different cell types, including those of the nerves. These cells are derived from human tissue and can be produced in large numbers for multiple experiments without the need to use animals. I will then artificially damage these cells and measure levels of periaxin and peripherin released after damage. Finally, I will measure the biomarkers in the blood of people with inflammatory neuropathies and compare levels with disorders of the central nervous system (brain and spinal cord) to ensure that peripherin and periaxin are specific to the peripheral nerve.Bench-to-bedside translation of my research findings will improve clinical and research aspects of the inflammatory neuropathies. On a clinical level, peripherin and periaxin will accurately measure peripheral nerve disease, assist with monitoring, identification of relapse and titration of treatment. Crucially, this will reduce side effects and long-term disability due to excessive or insufficient treatment respectively. Nerve-specific biomarkers will also make diagnosis of peripheral nerve disease more accurate, and will help predict degree and speed of recovery. On a research level, periaxin and peripherin will aid selection of patients for clinical trials, maximising efficiency of peripheral nerve research, and ultimately improving patient care.