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Dr Dorothea Sesardic, Dr Christine Escargueil and Dr Roland Fleck, National Institute for Biological Standards and Control (NIBSC)

Development of cell based assays as replacement assays for botulinum toxins and antitoxins

Abstract

Botulinum toxins are highly poisonous naturally occurring proteins produced by the bacterium Clostridium botulinum. These toxins act by blocking function in nerve cells which leads to paralysis and even death, although treatment is possible with antitoxins if they can be given to patients in time. In very small quantities however these neurotoxic proteins can be therapeutic, for example by blocking painful muscle spasms, and they are used for a variety of new medical applications, as well as for cosmetic treatments.

Before they can be used in humans, botulinum toxins and antitoxins must be tested for safety and potency. The most commonly used test for this involves mice in a procedure with lethality as an endpoint, classified by the Home Office as being of substantial severity. New methods are required to replace these tests with non-animal alternatives. Alternative tests are available but they are time consuming, only reflect one or two of several factors contributing to botulinum toxicity, and still use animal cells and tissues. One approach to avoid these limitations is to use models based on human cell lines which are differentiated into neuronal-like structures and capable of responding to the botulinum toxins.

In this study these differentiated cells will be used on micro-electrode arrays, in conjunction with cell imaging,and flow cytometry combined with immunodetection to investigate cell function and how this is affected by the toxin. This new approach should reflect the full action of the neurotoxins potentially replacing at least 70,000 mouse lethality assays each year in the UK alone.