ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2018) 15 14.17 | DOI: 10.1530/ey.15.14.17

Sobell Department of Motor Neuroscience, University College London Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK


To read the full abstract: Lancet 2017;390:1664-1675

Whoever could have imagined that a compound discovered as being secreted by enteroendocrine cells in the gut could have a role in treating Parkinson’s disease? GLP-1 does indeed have diverse actions on several peripheral organs (including tongue, stomach, adipose tissues, muscle, pancreas and liver) and on the brainstem to regulate food consumption and glycaemia. Pre-clinical studies in rodents had shown apparent effects of GLP-1 on promoting neurite outgrowth and protecting hippocampal neurons from apoptotic insult, and even stimulating adult neurogenesis, particularly of neurons positive for tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis. The positive findings of this randomised, placebo-controlled trial of exenatide, administered peripherally at licensed diabetes doses, open new treatment avenues for neurological diseases and highlight the remarkable gut-brain axis: the close synergy in biochemical signaling between these organs.

From a broader perspective, the identification of unanticipated alternative treatment targets for existing medicines can be lucrative for companies. Alternatively, the emergence of unanticipated off-target side effects can destroy a promising new agent, often late in the pharmacological pipeline after costly investment, and can prove much more costly for companies and patients if discovered by post-marketing surveillance. ‘Genomic target validation’ is an alternative hypothesis-free approach that aims to flush out unanticipated drug effects, whether good or bad, at a much earlier stage of drug development, and has attracted recent major investments https://www.gsk.com/en-gb/media/press-releases/gsk-and-23andme-sign-agreement-to-leverage-genetic-insights-for-the-development-of-novel-medicines/.

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