Chemical and Biological Therapeutic Approaches to Neurological Disorders Symposium


On Monday 18th April, the 3rd symposium on Chemical and Biological Therapeutic Approaches to Neurological Disorders took place at Burlington House in London. Dr Paul Beswick and I (Tristan Reuillon) represented the Sussex Drug Discovery Centre (SDDC) at this one day conference, organised by the Royal Society of Chemistry. Paul gave a talk on the use of structural biology for the design of ligands for glutamate ionotropic receptors, an approach which has been and is being used on different projects at the SDDC, while I presented a poster on recent developments in the field of AMPA receptor positive allosteric modulators.

Some of the leading researchers in the field of neuroscience were presenting, such as Dr Eric Karran, former head of research at Alzheimer Research UK now at AbbVie or Prof John Hardy from UCL, recent winner of the Breakthrough Prize in Life Sciences for his pioneering research into the genetic causes of Alzheimer’s disease (AD). Dementia was the major focus of the symposium, with Dr Eric Karran introducing the statistics on AD and giving a detailed overview of the different theories believed to underlie AD (amyloid-beta (Aβ) and tau pathologies). According to Dr Karran the readouts of some critical clinical trials on AD drugs within the next two years will be extremely important to understand if the drug discovery efforts have been heading in the right direction and to guide further the current research on dementia. Prof John Hardy presented the genetic causes behind AD and amyloid deposition, with an emphasis on some specific proteins, such as TREM2, which represent very attractive drug discovery targets. Prof Nigel Hooper from the University of Manchester presented research focussed on Aβ, trying to identify what forms of Aβ oligomers and fibrils are neurotoxic and trying to link the alpha-secretase ADAM10 with Aβ production. Finally Dr Suchira Bose from Eli Lilly gave an in-depth analysis of the tau pathophysiology and different modulations of this physiological pathway which could lead to novel therapeutic approaches to AD.

Other neurological disorders were also discussed during the symposium. Dr Hasane Ratni from Roche presented the discovery of RG7800, a drug currently tested in phase II clinical trials for the treatment of Spinal Muscular Atrophy, a rare neurodegenerative disease affecting mainly children. RG7800 acts as a SMN2 splicing modifier. Dr Richard Mead from the University of Sheffield talked about his current research on Motor Neuron Disease, also termed Amyotrophic Lateral Sclerosis, with a focus on the NRF2-ARE pathway, an indicator and modulator of oxidative stress in neurodegeneration. Different attempts to identify activators of this pathway, such as apomorphine, were discussed. The presentation of Dr Paul Beswick on glutamate potentiators was centred on the identification of novel drugs to treat the cognitive dysfunction associated with Schizophrenia, a major symptom, for which there is a clear unmet medical need. Finally, Prof Kristian Stromgaard from the University of Copenhagen, presented a few drug discovery approaches that his group has undertaken to disrupt protein-protein interactions in the CNS, such as the PSD-95-NMDA interaction. Owning to the lack of success in identifying small molecule hits, his research has focussed on peptidomimetics, which are surprisingly brain penetrant and are currently in preclinical development.

I found this symposium extremely interesting, with some fantastic and innovative research being disclosed, and would highly recommend it for anyone interested in neuroscience research. I hope to have given you through this blog article a flavour of the different topics which were discussed on that day and maybe tempted you to attend the 4th symposium in this series which will take place next year.

 

Blog written by Tristan Reuillon

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The Alzheimer’s Research UK (ARUK) conference 2016 took place in Manchester on the 8th and 9th of March. Researchers mostly from the UK, but also guest speakers from Germany and the US, presented their research that covered different fields of study related to Alzheimer’s disease (AD). However, the conference for the author of this blog already started the day before with the PhD day. This day was just for PhD students working on AD or AD related topics and gave them the opportunity to present their work in a more informal environment. The students presented their results in the form of posters or presentations and to the blog author’s delight also negative (or less “good looking”) results were presented which promoted vibrant discussion. Tea and lunch breaks were used to browse posters which pushed PhD students to get in touch with each other. The day was completed by presentations of academic and industrial representatives that gave insight into different career paths.

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Figure 1 | Sussex PhD students who participated in the conference. From left to right: Mahmoud, Karen, Saskia, Devkee, Lucas, Rebecca, Joanne and Luca.

With the PhD day already being a great success, the following days were sure to turn out to be as good. While more basic AD-related concepts and research were covered during the first day, the second day provided talks about new treatment approaches for dementia, as well as AD drug discovery and development. Two talks were in particular interesting:

Evidence is pointing towards inflammation processes that may trigger and influence AD pathology. One inflammation factor that seems involved and is activated in AD is the NLRP3 inflammasome (1). The NLRP3 inflammasome is a multiprotein complex which is formed inside macrophages and microglial cells and that catalyses the activation of caspase-1. Caspase-1 in return converts interleukin-1β (IL-1β) into its active form which is secreted and triggers an immune response. Most commonly, nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of inflammatory conditions that act through inhibition of cyclooxygenase 1 and/or 2. Dr David Brough and colleagues at the University of Manchester hypothesized that NSAIDs may supress inflammation through a mechanism dependent on NLRP3 inflammasome inhibition and thus could potentially be repurposed as inflammasome inhibitors. Screening identified fenamates (fenamic acid, mefenamic acid) to be able to block NLRP3 formation by inhibition of the volume-regulated anion channel (VRAC). Other NSAIDs such as ibuprofen or diclofenac did not show any effect on NLRP3 mediated inflammation. Nevertheless, the other NSAIDs may still exert a positive effect via alternative pathways. Prof Michael Heneka from the University of Bonn (Germany), who gave a talk on targeting innate immunity in AD, demonstrated that these NSAIDs are great activators of peroxisome proliferator-activated receptor gamma (PPAR-γ). Activation of PPAR-γ was shown in transgenic APP/PS1 mice to increase Aβ removal by microglial cells (2). The activating effect of NSAIDs on PPAR- γ may also explain their efficacy in reducing the risk of AD (3). Conclusively, NSAIDs may be an interesting class of anti-inflammatory drugs that could be repurposed in the treatment and/or prevention of AD.

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Figure 2 | Activation of the NLRP3 inflammasome and production of active IL-1β. Activation of microglial cells via the Toll-like receptor (TLR) or cytokine receptors induces the production of components of the NLRP3 inflammasome, as well as pro-IL-1β. Lysosomal damage by Aβ leads to assembly and activation of the inflammasome that in turn activates caspase-1. Caspase-1 processes pro-IL-1β to its bioactive form which is released. Picture from (3)

The second talk that strongly caught the interest of the author of this blog was the introduction of the Alzheimer’s Research UK Drug Discovery Alliance – a coordinated initiative between the ARUK, Oxford University, Cambridge University and University College London that aims to accelerate the identification for new treatment for AD and other forms of dementia. The Drug Discovery Alliance is especially interested in new and unexplored biological targets and in doing so is keen to hear from researchers across the research community about potential proteins, enzymes or pathways that play a role in AD. By combining the individual strengths of all the three university institutes, the alliance hopes to drive innovation in dementia drug discovery.

 

Blog writted by: Lucas Kraft

 

References

  1.            Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., Gelpi, E., Halle, A., Korte, M., Latz, E., and Golenbock, D. T. (2012) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 493, 674–678
  2.            Mandrekar-Colucci, S., Karlo, J. C., and Landreth, G. E. (2012) Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J. Neurosci. 32, 10117–28
  3.            Heneka, M. T., Golenbock, D. T., and Latz, E. (2015) Innate immunity in Alzheimer’s disease. Nat. Immunol. 16, 229–236