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Treating pain

16 November 2005

New ways to alleviate debilitating pain are being investigated in the Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology.

Many inflammatory and neuropathic pain states are resistant to current therapies. It has recently been shown that in many of these disease states there is a large increase in levels of a protein called Nerve Growth Factor (NGF). This protein exacerbates painful responses by sensitising sensory neurons or by activating inflammatory cells. NGF acts via a receptor, called tyrosine kinase (TrkA), present on the surface of sensory neurons. The Dawbarn/Allen group has identified the region on the TrkA receptor that binds to NGF. They have produced this small part of the protein (called TrkAD5) in bacteria and purified it to homogeneity, and have determined its structure by X-ray crystallography (Figure 1), in collaboration with Leo Brady in the Department of Biochemistry. In situations where there is inflammatory pain, injection of TrkAD5 binds to excess NGF, rendering it inactive and thereby alleviating the pain.

In addition, aspects of asthma relating to sensitisation of sensory neurons are currently untreatable. In a collaboration with Christine Nassenstein and Armin Braun, at the University of Hanover, the group have shown that TrkAD5 controls this aspect of asthma. Thus TrkAD5 is unique in that it is the only compound which has been able to do this.

This binding domain is covered by four University patents. The protein, renamed as REN1820, has been out-licensed to a pharmaceutical company for clinical application. In collaboration with a number of groups worldwide the Dawbarn/Allen group have shown that this protein is effective in models of interstitial cystitis, pancreatitis, inflammatory pain, neuropathic pain and asthma. The protein is now at the stage of technology transfer for large-scale production to GMP (good manufacturing practice). It is envisaged that REN1820 will initially be used for the treatment of interstitial cystitis by subcutaneous injection.

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