UKDP: Integrated DEmentiA research environment (IDEA)

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

The UK Dementias Platform (UKDP) is a radically new approach to dementias research. It brings together data from
around 2,000,000 study participants from 22 cohorts to try and discover the causes of dementia and to find out ways of
slowing it down. The platform has been funded to the level of £12M.
In this proposal we want to improve UK infrastructure for dementia research so that the most can be made of the
opportunity provided by UKDP. We wan to improve the infrastructure by buying important pieces of equipment that will put
the UK at the forefront of dementia research worldwide and by establishing networks of scientists who will work together to
make best use of the equipment.
The three themes of the proposal are imaging, informatics and stem cells.
For imaging we want to establish a network of PET/MR scanning facilities across the UK so that the molecular processes
going on inside the brain that cause dementia can be studied.
For informatics we want to be bring together bas many different types of data as possible and make it easy as possible for
scientists to use them
For stem cells we want to take cells form adults with and without dementia to find out how cells change as the dementias
process begins and progresses.
We believe these proposals will raise standards, reduce costs, and deliver innovative and coordinated research, making
the UK an internationally unique place to study dementia.

Technical Summary

Our objective is to achieve a step-change in UK dementia research capacity through establishing national networks of
existing and emerging centres of excellence in imaging, informatics and cell-biology.
The UK Dementias Platform (UKDP) is a radically new approach to dementias research, providing a highly efficient and
cost-effective translational pipeline from discovery through to early phase trials. UKDP will create closer synergy between
epidemiology and experimental medicine with the re-purposing of epidemiologic cohorts for trials readiness. The size and
depth of phenotyping available to UKDP will deliver a step-change in the complexity and granularity of dementia related
hypothesis testing and accelerate compound development.
Proposed here is an infrastructure of investment and collaboration. Underpinning UKDP is a critical mass of researchers
and resources that will work together to encourage, facilitate, and develop a fully integrated dementia dedicated UK
research environment. This will raise standards, reduce costs, and deliver innovative and coordinated research, to make
the UK an internationally unique research environment. Through its partnership with major academic centres and industry,
UKDP is well positioned to achieve this goal.
Building on the recent MRC investment in UKDP, we propose here to renew and extend the UKDP integrative research
environment with an advanced molecular imaging network strategically located to exploit UKDP cohorts. Also proposed is
an integrated informatics environment to facilitate the location of and access to both data and bio-samples. The third
proposal is for a stem-cells network to promote the use of this important and emerging technology. Each of these elements
adds value to existing infrastructure investments and fills significant gaps in the UK research landscape.

Planned Impact

The current proposal in in support of the UKDP and will become part of the the UKDP impact strategy.
In summary, the UKDP strategy to deliver pact is to develop networks of partnership to actively consult engage the UK
academic community in relation to dementia research focussing on the direction,
technologies and collaborations of the UKDP and the wider UK national infrastructure.
Our aim is to:

1) promote the best possible science
2) create momentum in dementias research by being inclusive of, and synergistic with, other initiatives.
Partnership discussions with industry are already underway with exchanges of ides, interests and needs between
academic and industry stakeholders. Industry have identified their need for access to conversion (early MVI to dementia
cohorts and for experimental medicine studies to conform to regulatory requirements.
We remain committed to raising the profile of contemporary debate about dementia and its treatment. We wish to
encourage a culture of commitment to solving this problem. By increasing awareness at all levels of society we intend to
leverage resources for the platform and for dementia research in general, to increase awareness of the need for earlier
interventions and better targeted treatment in general by health service providers and the public alike.
Engagement with the general public and with patients and carers is a very important part of our mission. This serves not
only to communicate our research findings and their relevance but also to address such issues as stigma in society and the
research culture in the NHS in relation to dementia and older people. In addition to using the platform web-site to
communicate to the general public, we will also liaise with charities and advocate groups such as Age UK and the
Alzheimer's Society to promote our work and findings and to engage them in shaping the work programme.
In addition we will have a dedicated free-phone number available 6 days a week and a communications officer at 50% FTE
over 5 years whose responsibility is to develop and implement a communications and public engagement strategy.

Publications

10 25 50
 
Description International 3Rs Proze 2018 - please see awards section for details of impact
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Member of expert panel advising the Dementia Discovery Fund for potential investments in autophagy research
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description Advancing the GLP-1 receptor as a target in Parkinson's disease
Amount £68,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 10/2018 
End 10/2019
 
Description Apollo Therapeutics
Amount £732,918 (GBP)
Organisation Apollo Therapeutics 
Sector Private
Country United Kingdom
Start 01/2020 
End 12/2021
 
Description CBD Solutions Research Grant
Amount $480,000 (USD)
Organisation Karin & Sten Mortstedt CBD Solutions AB 
Sector Private
Country Sweden
Start 07/2018 
End 12/2020
 
Description Capital Equipment Fund, CEF3
Amount £500,000 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 08/2019 
End 07/2020
 
Description EU Innovative Medicines Initiative
Amount € 900,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 06/2016 
End 05/2021
 
Description Eisai-UCL Collaboration Project TIG E
Amount £231,000 (GBP)
Organisation Eisai Ltd 
Sector Private
Country Japan
Start 11/2017 
End 04/2020
 
Description Elucidating early stage ALS pathomecanisms that drive mitochondrial dysfunction
Amount £1,046,186 (GBP)
Funding ID MR/S025898/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2020 
End 12/2023
 
Description Exploring the molecular mechanisms of KAT8/KANSL1-dependent regulation of mitophagy
Amount $19,374,424 (USD)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 03/2020 
End 08/2021
 
Description High Content Screening (HCS) platform for HD drug discovery
Amount £381,185 (GBP)
Organisation Takeda Pharmaceutical Company 
Sector Private
Country Japan
Start 12/2017 
End 12/2019
 
Description Investigating proteostasis in development and disease using iPSC neurons with MAPT mutations linked to FTD
Amount £107,034 (GBP)
Funding ID BB/S506886/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2018 
End 09/2022
 
Description Lysosome turnover in health, aging and disease
Amount £1,232,805 (GBP)
Funding ID 212216/Z/18/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2019 
End 05/2024
 
Description MRC Partnership Grant
Amount £1,220,774 (GBP)
Funding ID MR/N013255/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2016 
End 05/2019
 
Description Modeling Parkinson's disease in 2D and 3D.
Amount £82,300 (GBP)
Organisation MRC Doctoral Training Program 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 10/2021
 
Description Molecular Characterization of FAN1 Variation in Huntington's disease
Amount £163,169 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2017 
End 06/2018
 
Description Non cell autonomous Alzheimer's disease in iPSC derived cells - astrocyte reactivity and APP signalling
Amount £224,932 (GBP)
Funding ID 177986 
Organisation Alzheimer's Society 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2018 
End 02/2022
 
Description Research Grant
Amount £204,308 (GBP)
Organisation CBD Solutions 
Sector Private
Country United States
Start 07/2018 
End 12/2019
 
Description Senior Research Fellowship
Amount £420,000 (GBP)
Funding ID ARUK-SRF2016B-2 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description TDRF
Amount £151,213 (GBP)
Funding ID BB/P027431/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2018 
End 02/2019
 
Description Targeting autophagy dependence in pancreatic cancer
Amount £109,341 (GBP)
Funding ID 2018RIF_15 
Organisation Pancreatic Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2019 
End 09/2022
 
Description UCL Eisai collaboration
Amount £5,000,000 (GBP)
Organisation Eisai Ltd 
Sector Private
Country Japan
Start 11/2017 
End 04/2019
 
Description UCL RCIF Capital Equipment Fund 2018-19
Amount £155,000 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 09/2018 
 
Description UCL-Eisai Therapeutic Innovation Group: - Eisai Ltd: - UCL-Eisai Therapeutic Innovation Group (£ 60000; 2018 - 2019)
Amount £60,000 (GBP)
Funding ID 522585 
Organisation Eisai Ltd 
Sector Private
Country Japan
Start 08/2018 
End 09/2019
 
Description University of Pennsylvania Orphan Disease Center
Amount $51,020 (USD)
Funding ID MDBR-19-102-BPAN 
Organisation University of Pennsylvania 
Sector Academic/University
Country United States
Start 02/2019 
End 01/2020
 
Description WT Institutional Strategic Support Fund
Amount £65,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2015 
End 12/2017
 
Title AAV Vectors for CNS expression 
Description Investigation of the therapeutic potential of reduction of tau protein in CNS using truncated long non-coding RNA linked to the tau gene. Derivation of AAV9 vectors for CNS delivery of the long non-coding RNAs 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2018 
Provided To Others? No  
Impact Project in progress. Current outcome: Wide CNS distribution after AAV9 injection in mouse model with reduction in brain levels of tau. We expect accompanying therapeutic effect. 
 
Title Cellular FRET biosensor for tau aggregation 
Description This is a cellular model with co-expression of GFP- and RFP-tau and is a robust model to study tau aggregation and assess the therapeutic potential of anti-aggregation agents and antibodies 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2018 
Provided To Others? No  
Impact With this robust biosensor, we have shown the potential therapeutic anti-aggregation potential of anti-tau antibodies that we have developed. 
 
Title Stable cell lines for tau gene associated non-coding RNA genes 
Description Stable overexpression of non-coding RNA genes enables consistent cell-based model to investigate the downstream regulatory effects of these non-coding genes 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2015 
Provided To Others? No  
Impact Have succeeded in clarifying the precise role of the non-coding RNA genes in the post-transcriptional regulation of tau gene expression 
 
Description ARUK DDI 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution The UKDP is working closely with the ARUK Drug Discovery Institute with the aim to develop novel therapies for neurodegenerative disorders. Both networks collaborate closely in terms of drug discovery research and through exchange of knowledge, equipment and technologies.
Collaborator Contribution The UKDP is working closely with the ARUK Drug Discovery Institute with the aim to develop novel therapies for neurodegenerative disorders. Both networks collaborate closely in terms of drug discovery research and through exchange of knowledge, equipment and technologies.
Impact None yet
Start Year 2017
 
Description CBD clinicopathological classification 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Part of team to investigate clinico-pathological correlates in progression of corticobasal degeneration and pathological seeding species. Participating with expert input into project and assisting in experimental procedures.
Collaborator Contribution They have described markers of clinico-pathological progression of tauopathy in corticobasal degeneration (CBD) and obtained funding for neuropathological classification of CBD sub-types and established methodology to investigate pathological seeding and spread in postmortem material.
Impact Ongoing.
Start Year 2017
 
Description Dementia Platform UK Stem Cell Network 
Organisation Cardiff University
Department School of Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed a strategy for integrating stem cell neuronal research across 6 centres for harmonising and validating protocols, high content imaging of models, neurophysiology, genomics and proteomics,
Collaborator Contribution As above
Impact Two teaching technical workshops held at Oxford and Cambridge.
Start Year 2015
 
Description Dementia Platform UK Stem Cell Network 
Organisation University of Cambridge
Department Gurdon Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Developed a strategy for integrating stem cell neuronal research across 6 centres for harmonising and validating protocols, high content imaging of models, neurophysiology, genomics and proteomics,
Collaborator Contribution As above
Impact Two teaching technical workshops held at Oxford and Cambridge.
Start Year 2015
 
Description Dementia Platform UK Stem Cell Network 
Organisation University of Edinburgh
Department Centre for Clinical Brain Sciences (CCBS)
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed a strategy for integrating stem cell neuronal research across 6 centres for harmonising and validating protocols, high content imaging of models, neurophysiology, genomics and proteomics,
Collaborator Contribution As above
Impact Two teaching technical workshops held at Oxford and Cambridge.
Start Year 2015
 
Description Dementia Platform UK Stem Cell Network 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed a strategy for integrating stem cell neuronal research across 6 centres for harmonising and validating protocols, high content imaging of models, neurophysiology, genomics and proteomics,
Collaborator Contribution As above
Impact Two teaching technical workshops held at Oxford and Cambridge.
Start Year 2015
 
Description Dementia Platform UK Stem Cell Network 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed a strategy for integrating stem cell neuronal research across 6 centres for harmonising and validating protocols, high content imaging of models, neurophysiology, genomics and proteomics,
Collaborator Contribution As above
Impact Two teaching technical workshops held at Oxford and Cambridge.
Start Year 2015
 
Description Drug Discovery Approaches for Mitophagy Modulators 
Organisation Alzheimer's Research UK
Department UCL Drug Discovery Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We have had two joint grants to utilise a genetic siRNA and compound screen to find modulators of mitophagy. We have provided the original assays in low throughput and employed a research assistant based at the DDI to optimise in high throughput and perform the screens.
Collaborator Contribution The DDI provide expertise in screening, and the facilities and equipment necessary for high content screening (microscope, automated liquid handling etc.
Impact We received two grants from the UCL Transaltional research office - a therapeutic innovation fund, and a therapeutic acceleration support grant.
Start Year 2016
 
Description Gamma secretase stabilisiers 
Organisation Janssen Pharmaceutica NV
Country Belgium 
Sector Private 
PI Contribution Establishment of a high throughput screen to identify compounds that modulate gamma secretase enzyme activity.
Collaborator Contribution Supply of reagents (antibodies) and compound libraries
Impact The compound screen is currently being run. We hope to identify novel compounds to enable a drug discovery programme
Start Year 2018
 
Description Industry collaboration - drug discovery in iPSC derived ALS models 
Organisation Cerevance Ltd
Country United Kingdom 
Sector Private 
PI Contribution Based on a discovery made in our laboratory we proposed a platform utilising iPSC derived motor neurons to screen for modulators of early phenotypes. We provided the expertise, the platform and developed the screen in our laboratory.
Collaborator Contribution The partners provided resources for a postdoctoral scientist for 3 years, and also generated a gene edited control in their laboratory for use in the screen.
Impact This partnership resulted in a publication, and the outputs of the screen are currently being prepared for a further publication.
Start Year 2015
 
Description Mitophagy 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Establishment of a phenotypic assay to enable identification of novel pathways for mitophagy in Parkinsons disease
Collaborator Contribution Helen Plun Favreau. Deep knowledge of Parkinsons disease and mitophagy biology. Follow up biological validation of hits identified in the siRNA screen.
Impact a publication is being prepared
Start Year 2017
 
Description Modulation of astrocyte purinergic receptors to normalise neuronal hyper-excitability 
Organisation Dementia Discovery Fund
Country United Kingdom 
Sector Private 
PI Contribution The identification and validation of novel purinergic receptor antagonists expressed by astrocytes. The demonstration that such antagonists are able to normalise the neuronal hyperexcitability in brain slices from mouse models of Alzheimer's disease.
Collaborator Contribution Funding and support to enable this project, and the establishment of a new company - AstronauTx
Impact None so far
Start Year 2019
 
Description Modulation of astrocyte purinergic receptors to normalise neuronal hyper-excitability 
Organisation University of Edinburgh
Department Edinburgh Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution The identification and validation of novel purinergic receptor antagonists expressed by astrocytes. The demonstration that such antagonists are able to normalise the neuronal hyperexcitability in brain slices from mouse models of Alzheimer's disease.
Collaborator Contribution Funding and support to enable this project, and the establishment of a new company - AstronauTx
Impact None so far
Start Year 2019
 
Description Notum inhibitors 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Identification of small molecule inhibitors of the Wnt signaling inhibitor enzyme Notum
Collaborator Contribution Oxford - X ray crystal structure of Notum to enable the drug discovery Crick - generation of genetically modified mice for understanding of the functional rolel of notum
Impact Papers: Fish PV, Steadman, D, Bayle ED, Whiting PJ (2019). New Approaches for the Treatment of Alzheimer's Disease. Bioorg. Med. Chem Lett. 29: 125-131 Atkinson BN, Steadman D, Zhao, Sipthorp J, Vecchia L, Ruza RR, Jeganathan F, Lines G, Frew S, Monaghan A, Kjaer S, Bictash M, Jones EY, Fish PV. Discovery of 2-phenoxyacetamides as Inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray Fragment Screen. Med. Chem. Comm. Submitted February 2019.
Start Year 2017
 
Description Notum inhibitors 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Identification of small molecule inhibitors of the Wnt signaling inhibitor enzyme Notum
Collaborator Contribution Oxford - X ray crystal structure of Notum to enable the drug discovery Crick - generation of genetically modified mice for understanding of the functional rolel of notum
Impact Papers: Fish PV, Steadman, D, Bayle ED, Whiting PJ (2019). New Approaches for the Treatment of Alzheimer's Disease. Bioorg. Med. Chem Lett. 29: 125-131 Atkinson BN, Steadman D, Zhao, Sipthorp J, Vecchia L, Ruza RR, Jeganathan F, Lines G, Frew S, Monaghan A, Kjaer S, Bictash M, Jones EY, Fish PV. Discovery of 2-phenoxyacetamides as Inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray Fragment Screen. Med. Chem. Comm. Submitted February 2019.
Start Year 2017
 
Description PerkinElmer 
Organisation Perkin Elmer
Country United States 
Sector Private 
PI Contribution Closely working together on the development of high-content screening technologies. We provide expertise and knowledge.
Collaborator Contribution We have received free hardware and software upgrades, e.g. free 5x objective and software upgrades.
Impact This has enabled the use of additional technologies on the platform, e.g. Presiscan, FRET.
Start Year 2017
 
Description Proteomics analyses to detect proteins associated with lncRNA 
Organisation University College London
Department Structural Molecular Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide the ChIRP samples, including lncRNA with associated proteins, ready for mass spectrometry analyses. We then carry out a full data analysis and mining based on the initially processed proteomics data we get back from our collaborators.
Collaborator Contribution Our partner uses these samples to carry out high-sensitivity mass spectrometry analyses, including initial QC and data analyses.
Impact na
Start Year 2018
 
Description RNA dysregulation in ALS 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Myself: I am a Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, a top 3 hospital worldwide for neurological treatment. My clinical expertise is in ALS diagnosis and treatment, and co-directs clinical service. My scientific research focuses on developing human iPSC models for ALS that display reliable pathogenic phenotypes; our laboratory is one of the few internationally that produces robust cultures of both motor neurons and astrocytes. We have deeply characterised our cultures Our research is co-located at the Francis Crick Institute, UK's flagship center for basic biomedical research. Crick provides advanced core facilities ranging from scientific computing and sequencing to gene-editing and high-throughput screening. We have an outstanding track-record of collaboration: Ule and Patani have also collaborated for >10 years, exploring the impact of RNA-processing in neural development and ALS. In 2017, the three of us published a study characterizing robust phenotypes in ALS motor neurons and astrocytes (Hall et al Cell Reports 2017); this directly led to our current collaborative discovery of aberrant intron retention in ALS (Luisier et al Nature Communications in 2018 and later recognised by the Paulo Gontigo International Prize in Medicine 2018). I provide the ALS disease platform, including patient-derived iPSC, post-mortem samples, and mouse models. As an active neurologist, I will ultimately take molecular findings to the clinic, accessing consented patient material; he has industry partnerships (including Takeda, Cerevance and Ono), so we are poised to translate mechanistic insights from this project into drug discovery.
Collaborator Contribution Jernej Ule is Professor of Molecular Neurobiology; he pioneered CLIP techniques and has applied them to study RNAs bound by ALS-associated proteins, including TDP43 and FUS. Ule provides the expertise for the molecular work, splicing perturbations, CLIP and proteomic experiments. Nicholas Luscombe is Professor of Computational Biology studying transcriptional and post-transcriptional regulation and their use in controlling biological processes such as development; he performs detailed statistical analyses of large-scale datasets to decode the information contained in genome sequences. Luscombe performs all the computational analysis to build statistical models, integrating both primary and publicly available genomic datasets, as well as imaging data from the cellular experiments. Study designs arise from continuous discussions between us; colocation means that fresh insights are iteratively cycled between discovery, interpretation and planning with minimal delay.
Impact Grants MRC Senior Clinical Fellowship awarded in 2018 Prizes 03/19 International 3Rs Prize for 2018 09/18 International Paulo Gontijo Prize in Medicine for 2018 06/16 Faculty of Brain Sciences (UCL) Excellence Award in Scientific Communication Publications: 1. Smethurst P, Risse E, Tyzack G, Mitchell JS, Taha DM, Chen Y, Newcombe J, Collinge, Sidle K*, Patani R*. Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis. Brain. In Press (Corresponding author). 2. Pandya VA, Patani R*. Decoding the relationship between ageing and amyotrophic lateral sclerosis: a cellular perspective. Brain. 2019 Dec 18. pii: awz360. doi: 10.1093/brain/awz360. (Corresponding author). 3. Thelin EP, Hall CE, Tyzack GE, Frostell A, Giorgi-Coll S, Alam A, Carpenter KLH, Mitchell J, Tajsic T, Hutchinson PJ, Patani R*, Helmy A*. Delineating Astrocytic Cytokine Responses in a Human Stem Cell Model of Neural Trauma. J Neurotrauma. 2019 Sep 18. doi: 10.1089/neu.2019.6480. (Corresponding author). 4. Tyzack GE, Luisier R, Taha DM, Neeves J, Modic M, Mitchell JS, Meyer I, Greensmith L, Newcombe J, Ule J, Luscombe NM*, Patani R*. Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis. Brain. 2019 Sep 1;142(9):2572-2580. doi: 10.1093/brain/awz217. (Corresponding author). 5. Malik B, Devine H, Patani R, La Spada AR, Hanna MG, Greensmith L. Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy. Sci Rep. 2019 Mar 5;9(1):3539. doi: 10.1038/s41598-019-40118-3. 5. Ziff OJ, Patani R*. Harnessing cellular aging in human stem cell models of amyotrophic lateral sclerosis. Aging Cell. 2018 e12862. 6. Luisier R, Tyzack GE, Hall CE, Mitchell JS, Devine H, Taha DM, Malik B, Meyer I, Greensmith L, Newcombe J, Ule J, Luscombe NM*, Patani R*. Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS. Nature Communications. 2018 May 22;9(1):2010. (Corresponding author). 7. Peskett TR, Rau F, O'Driscoll J, Patani R, Lowe R, Saibil HR. A liquid to solid phase transition underlying pathological huntingtin exon1 aggregation. Molecular Cell. 2018 May 17;70(4):588-601.e6. 8. Maffioletti SM, Sarcar S, Henderson ABH, Mannhardt I, Pinton L, Moyle LA, Steele-Stallard H, Cappellari O, Wells KE, Ferrari G, Mitchell JS, Tyzack GE, Kotiadis VN, Khedr M, Ragazzi M, Wang W, Duchen MR, Patani R, Zammit PS, Wells DJ, Eschenhagen T, Tedesco FS.Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering. Cell Reports. 2018 Apr 17;23(3):899-908. 9. Kelley KW, Ben Haim L, Schirmer L, Tyzack GE, Tolman M, Miller JG, Tsai HH, Chang SM, Molofsky AV, Yang Y, Patani R, Lakatos A, Ullian EM, Rowitch DH.Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength. Neuron. 2018 Apr 18;98(2):306-319.e7. 10. Serio A, Patani R*. Concise Review: The Cellular Conspiracy of Amyotrophic Lateral Sclerosis. Stem Cells. 2018 Mar;36(3):293-303. 11. R. Simone, Balendra R, Moens TG, Preza E, Wilson KM, Heslegrave A, Jaramillo JG, Abdelkarim S, Clarke M, Woodling NS.... Patani R*, Fratta P*, Isaacs AM*. 'G-quadruplex- binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo'. EMBO Molecular Medicine. 2018 Jan;10(1):22-31. (joint senior and corresponding author). 12. Tyzack GE, Hall CE, Sibley CR, Cymes T, Forostyak S, Carlino G, Meyer I, Schiavo G, Zhang SC, Gibbons GM, Newcombe J, Patani R*, Lakatos A* 'EphB1 is a neuronal signal that induces a neuroprotective astrocyte state, but fails in ALS' Nature Communications 2017 Oct 27;8(1):1164. (*Joint senior and corresponding author). 13. Thelin EP, Hall CE, Gupta K, Carpenter KLH, Chandran S, Hutchinson PJ, Patani R*, Helmy A*. Elucidating pro-inflammatory cytokine responses following traumatic brain injury in a human stem cell model.Journal of Neurotrauma 2017 Oct 5. doi: 10.1089/neu.2017.5155. (*Joint senior and corresponding author). 14. Hall CE, Yao Z, Choi M, Tyzack GE, Serio A, Luisier R, Harley J, Preza E, Arber C, Crisp SJ, Watson PMD, Kullmann DM, Abramov AY, Wray S, Burley R, Loh SHY, Martins LM, Stevens MM, Luscombe NM, Sibley C, Lakatos A, Ule J, Gandhi S*, Patani R*. 'Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS'. Cell Reports 2017 May 30;19(9):1739-1749. (Corresponding author). 15. Soreq L, UK Brain Expression Consortium, North American Brain Expression Consortium, Rose J, Soreq E, Hardy J, Trabzuni D, Cookson MR, Smith C, Ryten M, Patani R*, Ule J*. 'Major shifts in glial regional identity are a transcriptional hallmark of human brain aging'. Cell Reports 2017 Jan 10;18(2):557-570. (*Joint senior and corresponding author). 12. Devine H, Patani R. 'The Translational Potential of Human Induced Pluripotent Stem Cells for Clinical Neurology'. Cell Biology and Toxicology 2017 Apr;33(2):129-144. 16. Smethurst P, Newcombe J, Troakes C, Simone R, Chen YR, Patani R, Sidle K. 'In vitro prion-like behaviour of TDP-43 in ALS'. Neurobiol Dis. 2016 S0969-9961(16)30195-4. 17. Tyzack G, Lakatos A, Patani R. 'Human Stem Cell-Derived Astrocytes: Specification and Relevance for Neurological Disorders'. Current Stem Cell Reports 2016 2:236-247. 18. Zirra A, Wiethoff S, Patani R. 'Neural conversion and patterning of human pluripotent stem cells: a developmental perspective'. Stem Cells International 2016 8291260. doi: 10.1155/2016/8291260. 19. Balendra R, Patani R. 'Quo vadis MND?'. World J Methodol. 2016 26;6(1):56-64. 20. Patani R. Generating Diverse Spinal Motor Neuron Subtypes from Human Pluripotent Stem Cells. Stem Cells International 2016 1036974. doi: 10.1155/2016/1036974. 21. Wiethoff S, Arber C, Li A, Wray S, Houlden H, Patani R. Using human induced pluripotent stem cells to model cerebellar disease: Hope and hype. J Neurogenet. 2015 Jun-Sep;29(2- 3):95-102. This work emphasises the importance of interdisciplinary and team science, integrating stem cell biology, developmental biology, neuropathology, bioinformatics and RNA biology.
Start Year 2018
 
Description Simon-Raj In vivo work 
Organisation University College London
Department Institute for Women's Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Indentification and characterisation of tau gene promoter associated long-non-coding RNA gene involved in regulation of tau gene. Design of active minimised variants and derivation of AAV expression vectors for in vivo work
Collaborator Contribution Maintenance of mouse colony, AAV injection and behavioural studies
Impact Ongoing. One publication has resulted from collaboration (PMID: 30081233)
Start Year 2016
 
Description TIGC anti-tau immunotherapy 
Organisation Eisai Ltd
Department Eisai London Research Laboratories
Country United Kingdom 
Sector Private 
PI Contribution UCL lead of collaborative project including conception, planning and development leading to clinical introduction of anti-tau passive immunisation in clinic.
Collaborator Contribution Worked collaboratively in pre-clinical development of successful drug candidate. Industrial partner completed validation, humanisation and toxicology of drug candidate and are now carrying out clinical trials.
Impact Published pre-clinical characterisation of clinical candidate: https://www.ncbi.nlm.nih.gov/pubmed/32019610 Patent Application filed: (US10358485B2)
Start Year 2014
 
Description Tau-based gene therapy for neurodegenerative disorders 
Organisation Karolinska University Hospital
Department Center for Molecular Medicine
Country Sweden 
Sector Hospitals 
PI Contribution We have developed vectors to test the concept of gene therapy directed at tau gene expression in slowing or halting the progress of tau-relaed neurodegeneration.
Collaborator Contribution Injection and study of mouse models for tauopathy
Impact None to date - still in progress
Start Year 2015
 
Title ANTI-TAU ANTIBODIES AND USES THEREOF 
Description Provided herein are antibodies that specifically bind Tau and methods of using the same. 
IP Reference WO2019077500 
Protection Patent application published
Year Protection Granted 2019
Licensed Commercial In Confidence
Impact E2814 antibody developed with TIG collaboration between UCL and Eisai. Pre-clinical studies leading to first-in-man trials (Phase 1) in Alzheimer's disease initiated in early 2020.
 
Title E2814 anti-tau Clinical Trial 
Description Therapeutic intervention Phase I clinical trials for Alzheimer's disease to commence in April 2019 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2019
Development Status Under active development/distribution
Impact Still under assessment 
 
Title lncRNAs and therapeutic reduction of tau 
Description Refined/truncated lncRNA transcript delivery in vivo by AAV vectors to test if tau is reduced and if there is any therapeutic benefits in animal models of tauopathies. Most recent funding from Brain Research Trust. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact Possibly using the same concept to regulate translation of other genes 
 
Company Name ASTRONAUTX LIMITED 
Description Dementia Discovery Fund supported company with a focus upon astrocytes as therapeutic targets for dementia. Has recently also gained funding from Albion Investments VC fund. 
Year Established 2019 
Impact None as yet
 
Description @PataniLab Twitter 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact We have over 1300 followers on Twitter and regularly tweet about updates from our lab
Year(s) Of Engagement Activity 2015,2016,2017,2018,2019,2020
URL https://twitter.com/PataniLab
 
Description FCS single molecule workshop in Hyderabad 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact About 300 students from India and from other countries attended this workshop and scientific conference, many of whom came from structurally disadvantaged backgrounds. This workshop introduces postgraduate and undergraduate students to single molecule spectroscopy techniques both in theory and in practice. In addition to lectures and seminars, the students got the unique opportunity to build their own microscopy setups and have extensive hands-on tutoring on super-resolution microscopy, Raman spectroscopy, and single molecule dynamics. Protein folding and misfolding processes in diseases like Alzheimer and prion disease were a central application of these techniques. In the conference following the workshop, the students had the opportunity to present their own research and discuss with leaders in the fields of single molecule spectroscopy and protein misfolding. The event was also attended by international companies and Indian science policy makers.
Year(s) Of Engagement Activity 2019
URL https://fcs2019.tifrh.res.in/
 
Description High-Content Biology Lab Opening Symposium 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact 120 researchers attended the Opening Symposium for the High-Content Screening facility, which sparked interest in accessing the facility from academics and industry partners.
Year(s) Of Engagement Activity 2018
 
Description Lab Tour for Pancreatic Cancer UK and General Public 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact This event was a Lab Tour, sponsored by Pancreatic Cancer UK, for supporters, patients and carers of patients with Pancreatic Cancer. I have presented my lab/facility in a talk and a lab tour, which sparked a lively discussion with the attendees.
Year(s) Of Engagement Activity 2019
 
Description MRC DPUK Stem Cell Partnership workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact 2 day workshop for postdocs, PhD students and PIs on biology of neurodegenerative disease biology and use of stem cell derived models to study these. Researchers/students from 10-15 HEI attended
Year(s) Of Engagement Activity 2018
 
Description Panel discussion at Royal Institution 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Making monsters? Ethical gene editing

Modern stem cell and embryology research has the potential to revolutionise medicine, but some see it as 'playing God'. I was part of a panel of scientists and policy experts discussing the latest developments in genetic medicine and whether we are ready for the ethical challenges these technologies raise.
Year(s) Of Engagement Activity 2018
URL https://www.rigb.org/whats-on/events-2018/april/public-making-monsters-ethical-gene-editing
 
Description School Visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact About 20 A-level school children visited the High-Content Biology Laboratory and were given an introduction to lab equipment and work practices. The school reported increased interested in STEM based subjects from their pupils following the visit.
Year(s) Of Engagement Activity 2020
 
Description School visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Approx 20 school children visited the screening lab and were given hands-on introduction to research in my lab.
Year(s) Of Engagement Activity 2019
 
Description Scientific Advisory Board Expert Panel for the Dementia Discovery Fund 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact The Scientific Advisory Board of the Dementia Discovery Fund in collaboration with Alzheimers Research UK, invited me as an expert panel member to discuss the role of Autophagy in Alzheimer's disease. The SAB (composed of leading experts in the pharmaceutical industry and charities) explored the possbility to invest in the development of autophagy modulating drugs for treatment of Alzheimer's disease. This discussion had an immediate impact on funding decisions and the policy of the Dementia Discovery Fund going forward in this area.
Year(s) Of Engagement Activity 2019
 
Description Single cell imaging 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Have for the last three years had a group of year 12 students from Brighton College visit my lab and be introduced to the work we do on Dementia. We give a talk and then they visit different parts of the lab where my lab members tell they what experiments they do and what equipment we use. We also give out leaflets from the ARUK and ASoc. We discuss careers in neuroscience and especially dementia research. I have also had individual students undertake work experience in my lab for 2-5 days where we teach them about dementia and how we do experiments. They are introduced to the equipment and where and how we get funding to conduct our research.
Year(s) Of Engagement Activity 2016,2017,2018
 
Description Talk on research as a career for girls 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact As a female in science, I gave a talk to school children at Leytonstone school on career as a researcher in neurodegeneration.
Year(s) Of Engagement Activity 2019
 
Description visit by sixth form students to our labs 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 15 sixth form students from local state schools studying science with interest in medicine, neuroscience. Saw brain in brain bank, histology, stem cell derived neuronal cultures and questioned phd student, postdoc, medics and a patient with neurodegenerative disease.
Year(s) Of Engagement Activity 2018,2019