Non-Clinical Lecturer in Translational Neuroscience
Kenneth Snowman MNDA Lectureship
In collaboration with Professor Pamela Shaw, Dr Mead has developed and implemented a strategy for small molecule drug development within SITraN. This has enabled the identification of a CNS penetrating Nrf2-ARE pathway activating molecule with activity in MND/ALS preclinical models which is suitable for further clinical development (figure 1). Dr Mead and Professor Shaw have taken this compound from discovery through to orphan designation, with the European Medicines Agency, for treatment of MND/ALS.
Dr Mead is also interested in refining the screening methodology in preclinical models of ALS with particular regard to addressing variability issues, improving readouts, and reducing numbers and the time required to obtain robust data (PLoS One 2011. 6(8), e23244). Dr Mead has assessed a range of therapeutic approaches in this model over the past 7 years.
Research focused on drug discovery in motor neurone disease and amyotrophic lateral sclerosis (MND/ALS), from target identification, through in vitro screening to in vivo disease model testing. Specific areas include:
- Pharmacological manipulation of in vitro and in vivo model systems to dissect mechanisms in MND
- Improving screening methodologies, evolving new in vivo screening paradigms with improved welfare, reduced biological variation and faster throughput
- Target identification and traditional high throughput screening
- Development and screening of phenotypic assays using high content imaging
- Identification of ‘translational’ biomarkers, applicable in both preclinical and clinical settings
- Investigating novel cell therapy paradigms in MND/ALS
- Assist in the design and execution of therapeutic studies in the spinal muscular atrophy (SMA) preclinical model.
1. Identification of novel, non-reactive small molecule activators of the Nrf2-ARE pathway.
The Nrf2-ARE pathway (figure 1) is a key endogenous system for increasing cellular defences against oxidative stress. Small molecules that activate this pathway generally react with sulphydryl (SH) groups on Keap1, the cytoplasmic inhibitor of Nrf2. We have developed fluorescence polarisation assays to probe the interaction between Nrf2 and Keap1 with the goal of screening focussed libraries for their ability to disrupt this interaction as opposed to reacting with SH groups on Keap1.
2. Screening for modifiers of TDP43 localisation.
We have access to MND patient fibroblasts which show mis-localisation of TDP43 (figure 2) and are developing high-content, image based screens which can measure this mis-localisation, with the ultimate goal of screening for compounds that can correct this defect.
3. Anti-Inflammatory therapy in ALS.
Given the well described role of non-neuronal cells such as astrocytes and microglia in driving disease progression and inflammation in MND/ALS, we are testing a range of anti-inflammatory therapies in our pre-clinical ALS/MND model.
Medical Research Council
Motor Neuron Disease Association, UK
Family of Kenneth Snowman
Spinal Muscular Atrophy Trust
Figure 1. The Nrf2-ARE anti-oxidant response pathway. Triggered by oxidative stress or electrophilic small molecules, a conformational change in Keap1 leads to reduced binding of Nrf2 to the Keap1-based E3 ubiquitin ligase complex which leads to a net transfer of Nrf2 to the nucleus and increased transcription of a range of genes involved in defence against oxidative stress and cellular survival.
Figure 2. TDP43 localisation in ALS patient fibroblasts. Immunofluoresence staining for TDP43 (green), nuclei (blue, Hoescht), and α-tubulin (red). Merged image (bottom right panel) shows most nuclei have lost TDP-43 staining (black arrowheads) whereas a few retain nuclear staining (white arrowheads). In control patient fibroblasts a much higher proportion of nuclei retain TDP43 staining.
- Yuri Ciervo, PhD Student
- Nazia Maroof, Postdoctoral Research Associate
- Heledd Brown-Wright, PhD student
Mead RJ, Higginbottom A, Allen SP, Kirby J, Bennett E, Barber SC, Heath PR, Coluccia A, Patel N, Gardner I, Brancale A, Grierson AJ and Shaw PJ. S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis. Free Radic Biol Med 2013. 61C, 438-452.
Mead RJ, Bennet E, , Kennerly A, Sharp P, Sunyach C, Kasher P, Berwick J, Pettmann B, Battaglia G, Azzouz M, Grierson A, Shaw PJ. Optimisation of pre-clinical pharmacology studies in the SOD1G93A transgenic mouse model of Motor Neuron Disease. 2010. PLoS One 2011. 6(8), e23244.
Barber SC, Higginbottom A, Mead RJ, Barber S and Shaw PJ. (2009) An in vitro screening cascade to identify neuroprotective antioxidants in ALS. Free Radical Biology and Medicine 2009. 46(8), 1127-38.
Valori CF, Ning K, Wyles M, Mead RJ, Grierson AJ, Shaw PJ and Azzouz M. Systemic Delivery of scAAV9 Expressing SMN Prolongs Survival in a Model of Spinal Muscular Atrophy. Sci Transl Med 2010. 2, 35-42.
Mead RJ, Neal JW, Griffiths MR, Linington C, Botto M, Lasmmann H and Morgan BP. (2004). Deficiency of the complement regulator CD59a enhances disease severity, demyelination, and axonal injury in murine acute experimental allergic encephalomyelitis. Laboratory Investigation 84 (1), 21-28.
Mead RJ, Singaroah S, Neal, JW, Lasmmann H and Morgan BP. (2002) The membrane attack complex of complement causes severe demyelination in association with axonal injury. Journal of Immunology 168, 458-465.
Method for the treatment of Multiple Sclerosis by Inhibiting IL17 activity. Inventors Christie MI, Mead RJ, Robinson MK, Rapecki, SE. (2005) EP1687026 2006-08-09. WO2005051422. CA2544920. AU2004292393.
Therapeutics for neurological disorders. Inventors Shaw P, Mead R, Higginbottom A, Barber SC (2010). Publication number WO2010046710 (A1) describing NRF2 activating compounds for treatment of neurodegenerative diseases.
Knowledge exchange champion, department of Neuroscience
Neuroscience representative, Medical School Athena Swan Committee
2013 - Present: Kenneth Snowman-MND Association Lecturer in Translational Neuroscience
2010- 2013: SITraN Senior Research fellow in Translational Neuroscience, University of Sheffield, UK.
2005-2010: Postdoctoral Research Fellow, University of Sheffield, UK.
2002-2004: Pharmacology Team leader, Celltech/UCB, Cambridge, UK.
2001-2002: Postdoctoral research assistant, Department of Biochemistry, University of Wales College of Medicine, Cardiff, UK.
1998-2001: PhD (Neuroimmunology), University of Wales College of Medicine, Cardiff, UK.
Dr Mead obtained a PhD in Neuroimmunology from the University of Cardiff in 2001 where he identified the critical role of the terminal complex of the complement cascade in mediating demyelination in preclinical models of multiple sclerosis (J. Immunol. 168, 458-465; Laboratory Investigation 84 (1), 21-28). He then made the jump to industry working for Celltech (now part of UCB Pharma) first as a pharmacologist and then pharmacology team leader responsible for preclinical models of multiple sclerosis (MS). He was part of the first team to identify the critical role of IL17 in the development of EAE (Patent WO2005051422) and generated data which lead to the nomination of a pre-clinical candidate into phase I clinical trials for MS.
He joined the Neuroscience Department in Sheffield in 2005 with a Wellcome Trust Value in People award and has been instrumental in establishing the in vitro and preclinical small molecule screening programmes for Motor Neuron Disease (see references below) which has lead to the identification of a clinical candidate for MND. He has now taken up a Research Fellowship in Translational Neuroscience within SITraN.
I teach on the MSc courses in Translational Neuroscience and Molecular Medicine focussing on preclinical study design, analysis of motor function, statistics and drug development. I enjoy training and supervising MSc and BMedSci students on research projects. I also do some scientific outreach work in local schools as a speaker for Understanding Animal Research.