CoEN Developing preclinical and clinical biomarkers of NRF2 pathway activation for therapeutic application in neurodegenerative diseases.
Lead Research Organisation:
University of Sheffield
Department Name: Neurosciences
Abstract
Neurodegenerative diseases such as Alzheimer's (AD) and motor neuron disease (ALS/MND) cause cell death of different populations of nerve cells. These conditions are very distressing for sufferers and their families. There is a severe lack of treatments available to slow disease progression and clinical trials have had high failure rates partly because there is no way to demonstrate that a drug is reaching the nervous system in the right amounts to protect the nerve cells from injury. Although the underlying causes that trigger these diseases are complex (multiple genes and environmental factors), there is substantial overlap in the cell pathways that lead to neurodegeneration.
This project is focused on a master cellular pathway (sometimes called the programmed cell-life pathway) controlled by a molecule NRF2 that promotes cell survival in the face of stresses such as oxidative stress, inflammation, and failure of the energy-generating and protein quality-control pathways within neurons which are known to contribute to neurodegeneration. Our aim is to develop MRI imaging and body fluid markers to show NRF2-activating drugs working in the body. These results will be applied later in clinical trials to test the effectiveness of NRF2 activators for patients with MND and AD.
This project is focused on a master cellular pathway (sometimes called the programmed cell-life pathway) controlled by a molecule NRF2 that promotes cell survival in the face of stresses such as oxidative stress, inflammation, and failure of the energy-generating and protein quality-control pathways within neurons which are known to contribute to neurodegeneration. Our aim is to develop MRI imaging and body fluid markers to show NRF2-activating drugs working in the body. These results will be applied later in clinical trials to test the effectiveness of NRF2 activators for patients with MND and AD.
Technical Summary
There is an urgent need for effective neuroprotective therapies for neurodegenerative disorders including motor neuron disease and Alzheimer's disease. The heterogeneity and complexity of these disorders have proved major challenges for therapy development. However, in both disorders neuronal injury involves a combination of age-related attenuation of protective responses; oxidative stress; mitochondrial dysfunction; dysregulation of proteostasis and neuroinflammation. In the presence of such cellular stresses, an up-regulation of the NRF2 signalling pathway increases the expression of an array of cytoprotective genes. This response is attenuated during ageing and also in MND and AD, as well as in models of these disorders. Compelling evidence has emerged from robust model systems, with major contributions from the two teams underpinning this application, that NRF2 activation has positive benefits in protecting neurons from injury in MND and AD.
The overall objectives are to develop multiple biochemical, transcriptomic and imaging biomarkers in robust animal models of MND and AD and linked with evaluation in human biosamples and imaging studies, to determine target engagement and indices of therapeutic efficacy of two NRF2-activating compounds (S-apomorphine and dimethyl fumarate) for future translation into human experimental medicine studies. Such 'translational biomarkers' are regarded as critical parameters for successful drug development.
The overall objectives are to develop multiple biochemical, transcriptomic and imaging biomarkers in robust animal models of MND and AD and linked with evaluation in human biosamples and imaging studies, to determine target engagement and indices of therapeutic efficacy of two NRF2-activating compounds (S-apomorphine and dimethyl fumarate) for future translation into human experimental medicine studies. Such 'translational biomarkers' are regarded as critical parameters for successful drug development.
Planned Impact
We will conduct the first proteomic based study of treatment effect and oxidative protein modification in CSF of ALS patients. Currently multiple NRF2 activators are in clinical development and as far as we are aware, trials have moved forward without demonstrating target engagement in the CNS. Our methodology will be made widely available to any group wishing to take NRF2 activators into clinical development. A University of Sheffield spin-out, Keapstone Therapeutics (RJM and PJS founders) is in the early stages of developing novel NRF2 activators for ALS and Parkinson's disease. Other companies such as Reata Pharmaceuticals are developing NRF2 activators in trials of Friedreich's ataxia and an Australian academic clinical trial of Dimethyl Fumarate is planned in ALS. Given the high level of interest, we consider that the translational methodologies outlined here will be key in determining the success of this approach and extending our understanding of the NRF2 signalling pathway in therapy development for neurodegenerative diseases.
Publications
Balendra R
(2023)
Comparison Of King's Clinical Staging In Multinational Amyotrophic Lateral Sclerosis Cohorts.
in Amyotrophic lateral sclerosis & frontotemporal degeneration
Jiménez-Villegas J
(2022)
Dipeptide Repeat Pathology in C9orf72-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance.
in Antioxidants (Basel, Switzerland)
Thompson AG
(2022)
Multicentre appraisal of amyotrophic lateral sclerosis biofluid biomarkers shows primacy of blood neurofilament light chain.
in Brain communications
Jiménez-Villegas J
(2021)
NRF2 as a therapeutic opportunity to impact in the molecular roadmap of ALS.
in Free radical biology & medicine
Pham TK
(2021)
Proteomic Approaches to Study Cysteine Oxidation: Applications in Neurodegenerative Diseases.
in Frontiers in molecular neuroscience
Verber NS
(2019)
Biomarkers in Motor Neuron Disease: A State of the Art Review.
in Frontiers in neurology
Benson BC
(2021)
Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis.
in Frontiers in neuroscience
Anton A
(2022)
Assessment of the Precision in Measuring Glutathione at 3 T With a MEGA-PRESS Sequence in Primary Motor Cortex and Occipital Cortex.
in Journal of magnetic resonance imaging : JMRI
Jenkins TM
(2020)
Longitudinal multi-modal muscle-based biomarker assessment in motor neuron disease.
in Journal of neurology
Description | AMS horizon scanning workshop |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Development of M102 to Investigational New Drug (IND) Stage for Initiation of Phase 1 Clinical Trials for Treating Amyotrophic Lateral Sclerosis (ALS). |
Amount | $1,475,101 (USD) |
Organisation | Department of Defense |
Sector | Public |
Country | United States |
Start |
Description | FightMND Australia Development of M102 for the treatment of MND |
Amount | £553,105 (GBP) |
Organisation | FightMND Australia |
Sector | Charity/Non Profit |
Country | Australia |
Start |
Description | MRC DPFS MICA-M102 a combined NRF2 and HSF1 activator for the treatment of motor neuron disease. |
Amount | £1,593,902 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start |
Title | CSF, blood and skin samples from MND patients and controls |
Description | 24 patients with MND, 13 with longitudinal samples collected 4 months later and 20 healthy controls, 12 with longitudinal samples collected 4 months later donated biological samples of CSF, blood (whole blood, serum, plasma, DNA, RNA, PBMC, genetic panel NGS) and skin biopsies for fibroblast reprogramming. |
Type Of Material | Biological samples |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | The samples have contributed towards a collaboration with Quell Therapeutics to identify targets for CAR Tregs as a therapeutic strategy in MND. |
Title | Additional file 11 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 11 : Table S9. mRNA nuclear export analysis in patient-derived neurons. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_11_of_SRSF1-dependent_inhibitio... |
Title | Additional file 11 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 11 : Table S9. mRNA nuclear export analysis in patient-derived neurons. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_11_of_SRSF1-dependent_inhibitio... |
Title | Additional file 13 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 13 : Table S10. Differentially-expressed transcripts in Drosophila |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_13_of_SRSF1-dependent_inhibitio... |
Title | Additional file 13 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 13 : Table S10. Differentially-expressed transcripts in Drosophila |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_13_of_SRSF1-dependent_inhibitio... |
Title | Additional file 14 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 14 : Table S11. Gene ontology analysis in Drosophila |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_14_of_SRSF1-dependent_inhibitio... |
Title | Additional file 14 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 14 : Table S11. Gene ontology analysis in Drosophila |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_14_of_SRSF1-dependent_inhibitio... |
Title | Additional file 17 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 17 : Table S12. C9ORF72-ALS disease-modifying gene expression signature. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_17_of_SRSF1-dependent_inhibitio... |
Title | Additional file 17 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 17 : Table S12. C9ORF72-ALS disease-modifying gene expression signature. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_17_of_SRSF1-dependent_inhibitio... |
Title | Additional file 18 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 18 : Table S13. Conserved human-fly gene expression changes. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_18_of_SRSF1-dependent_inhibitio... |
Title | Additional file 18 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 18 : Table S13. Conserved human-fly gene expression changes. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_18_of_SRSF1-dependent_inhibitio... |
Title | Additional file 2 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 2 : Table S1. RNA-seq statistics. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_2_of_SRSF1-dependent_inhibition... |
Title | Additional file 2 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 2 : Table S1. RNA-seq statistics. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_2_of_SRSF1-dependent_inhibition... |
Title | Additional file 3 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 3 : Table S2. Annotated quantified transcripts for RSEM>10. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_3_of_SRSF1-dependent_inhibition... |
Title | Additional file 3 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 3 : Table S2. Annotated quantified transcripts for RSEM>10. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_3_of_SRSF1-dependent_inhibition... |
Title | Additional file 4 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 4 : Table S3. Common cell marker counts. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_4_of_SRSF1-dependent_inhibition... |
Title | Additional file 4 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 4 : Table S3. Common cell marker counts. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_4_of_SRSF1-dependent_inhibition... |
Title | Additional file 5 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 5 : Table S4. SRSF1 transcript counts. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_5_of_SRSF1-dependent_inhibition... |
Title | Additional file 5 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 5 : Table S4. SRSF1 transcript counts. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_5_of_SRSF1-dependent_inhibition... |
Title | Additional file 6 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 6 : Table S5. Differentially-expressed transcripts in patient-derived neurons. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_6_of_SRSF1-dependent_inhibition... |
Title | Additional file 6 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 6 : Table S5. Differentially-expressed transcripts in patient-derived neurons. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_6_of_SRSF1-dependent_inhibition... |
Title | Additional file 7 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 7 : Table S6. Gene ontology analysis in patient-derived neurons. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_7_of_SRSF1-dependent_inhibition... |
Title | Additional file 7 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 7 : Table S6. Gene ontology analysis in patient-derived neurons. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_7_of_SRSF1-dependent_inhibition... |
Title | Additional file 9 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 9 : Table S7. Splicing analysis in patient-derived neurons. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_9_of_SRSF1-dependent_inhibition... |
Title | Additional file 9 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis |
Description | Additional file 9 : Table S7. Splicing analysis in patient-derived neurons. |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://springernature.figshare.com/articles/dataset/Additional_file_9_of_SRSF1-dependent_inhibition... |
Description | Partnership with Aclipse Therapeutics to develop M102 towards first-in-human clinical trial |
Organisation | Aclipse |
Country | United States |
Sector | Private |
PI Contribution | I led a research team in the discovery and development of M102, a dual NRF2 and HSP1 activator that emerged as a neuroprotective agent from a drug screen at SITraN. This received orphan drug designation from the European Medicines agency. M102 improved motor function in MND mice models and was shown to be safe in initial toxicology studies. I was on the Aclipse NRF2 clinical advisory board for the development towards clinical trials for M102. I have led and contributed to a number of grants to develop M102 towards biomarker supported first-in-man clinical trial readiness: 1. MRC Pathfinder CoEN Developing preclinical and clinical biomarkers of NRF2 pathway activation for therapeutic application in neurodegenerative diseases. PI 2. MRC DPFS 2020-2023 £1,593,902-77 (plus £1,781,415 contribution from ACLIPSE Therapeutics). MICA-M102 a combined NRF2 and HSF1 activator for the treatment of motor neuron disease. Co-PI. 3. FightMND 2020-2022 Australian $1,000,000 (£553,105). (Sheffield component £180,000) Development of M102 for the treatment of MND. Co-applicant 4. US Department of Defence (DoD) 2021-2023 £1,200,000 (Sheffield component £341,381). Therapeutic development award. Co-applicant. |
Collaborator Contribution | Aclipse has licensed intellectual property on M102 from the University of Sheffield and led on work to develop M102 as an investigational compound (US Department of Defence (DoD) 2021-2023 £1,200,000 Therapeutic development award). |
Impact | Mead, R.J., Shan, N., Reiser, H.J. et al. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov 22, 185-212 (2023). https://doi.org/10.1038/s41573-022-00612-2 |
Start Year | 2017 |
Title | TREATMENT OF NEUROLOGICAL DISEASES |
Description | The invention is directed to 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-l0,l l-diol for the treatment of diseases mediated by protein misfolding, heat shock factor 1 pathways, or nuclear erythroid 2-r elated factor 2 pathways. |
IP Reference | WO2020081973 |
Protection | Patent application published |
Year Protection Granted | 2020 |
Licensed | Yes |
Impact | The patent is licensed to Aclipse Therapeutics (USA). It covers the mechanism of action of a drug identified at SITraN for the treatment of neurodegenerative diseases, including ALS. Dr Richard Mead, Dr Laura Ferraiuolo and Professor Pamela Shaw secured an MRC DPFS award of £1.6M with long-time collaborator, US SME, Aclipse Therapeutics. Aclipse are contributing cash and in-kind of £1,78M to the project which aims to complete pre-clinical development of M102 (S [+] apomorphine) in preparation f |
Description | 14th UK Annual Neuromuscular Translational Research Conference (Virtual meeting), March 2021. New therapies for motor neuron disease. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Attracting in excess of 200 basic scientists and clinical scientists involved in neuromuscular disease research, this event is designed as a scientific meeting to promote and share cutting edge clinical and scientific advances in the neuromuscular field, and to encourage new research and collaborations. |
Year(s) Of Engagement Activity | 2021 |
URL | https://treat-nmd.org/event/14th-neuromuscular-translational-research-conference-2021/ |
Description | Annual General Meeting of the Manchester Motor Neurone Disease Association, Manchester, April 2022. "Update on research developments from SITraN 2021-2022". |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I gave an overview of research developments in MND in SITraN to the Manchester MNDA branch including updating on progress in clinical trials for MND, an orthosis co-design project development, biomarkers and infrastructure projects. The membership of local MNDA branches contribute significantly as healthy control volunteers for biosampling studies such as AMBRoSIA, so their AGMs are a good platform to provide an update on progress and thank participants for their support. |
Year(s) Of Engagement Activity | 2022 |
Description | Article featuring the work carried out by my laboratory in the March issue of Scitech Europa (PanEuropeanNetwork) |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | The PanEuropean Network aims to provide news and developments from across the entire spectrum of the European science and technology community. I was invited to submit an article about the work my lab carries out with industry and the support of EU funding. The audience of the journal is composed of EU commissioners and policy makers as well as scientists and the wider audience. |
Year(s) Of Engagement Activity | 2018 |
URL | http://edition.pagesuite-professional.co.uk/html5/reader/production/default.aspx?pubname=&edid=0e6f6... |
Description | Association of British Neurologists meeting Harrogate May 2022. A novel proposed panel of inflammatory and redox genes as biomarkers in amyotrophic lateral sclerosis |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | A poster presentation for the Association of British Neurologists, which has 1500 members |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.theabn.org/page/annualmeeting2022 |
Description | Birmingham Neurology Department Seminar Series, December 2023 - Motor Neuron Disease: a neurodegenerative disorder poised for successful therapy development. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Gave a seminar for Neurologists highlighting advances in understanding the genetic underpinnings of MND, the importance of disease stratification, biomarker development and systematic patient biosamples. I highlighted M102, a dual NRF2 and HSP1 activator as a biomarker supported therapy developing towards first in human trials and targeting SRSF1 to prevent the nuclear export of C9ORF72 transcripts as examples. |
Year(s) Of Engagement Activity | 2023 |
Description | Campaign Spotlight University of Sheffield. MDH Phase 1 infrastructure: new building. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Supporters |
Results and Impact | This was an influential presentation to promote the creation of a sister building to SITraN to expand our translational neuroscience activities as the primary project for the University of Sheffield Campaign and Alumni Relations team to help kickstart fundraising for £10m towards the project. The presentation helped to crystalize the vision and importance of the mission in the minds of the CAR team and 8 months on we several major donations have brought us to £6m of the goal. The presentation included details of the drug development pipeline at SITraN including the M102 project supported by biomarkers for NRF2 activation developed under the CoEN award. |
Year(s) Of Engagement Activity | 2023 |
Description | European Network to Cure ALS (ENCALS) Edinburgh 2022 (C48) Reprogrammed astrocytes from a C9-ALS family with variable penetrance display differential C9orf72 pathology and motor neuron toxicity in co-culture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presentation to ENCALS delegates |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.encals.eu/meetings/encals-meeting-2022-edinburgh-scotland/ |
Description | European Network to Cure ALS (ENCALS) Edinburgh 2022 (C50) Use of Next Generation Sequencing to Elucidate the Genetics of Monomelic Amyotrophy (MMA) in Bangladesh and UK patients |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presentation to ENCALS delegates |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.encals.eu/meetings/encals-meeting-2022-edinburgh-scotland/ |
Description | European Network to Cure ALS (ENCALS) Edinburgh 2022 (D77) Evaluation of M102, a dual NRF2 and HSF1 activator, as a Novel Therapeutic in Amyotrophic Lateral Sclerosis (ALS) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presentation to ENCALS delegates |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.encals.eu/meetings/encals-meeting-2022-edinburgh-scotland/ |
Description | European Network to Cure ALS (ENCALS) Edinburgh 2022 (E118) A novel proposed panel of inflammatory and redox genes as biomarkers in amyotrophic lateral |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presentation to ENCALS delegates |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.encals.eu/meetings/encals-meeting-2022-edinburgh-scotland/ |
Description | Focus on ALS Symposium, Genoa Italy, September 2018. Opening plenary lecture. A translational neuroscience approach to improve outcomes in ALS/MND: The journey so far and future prospects. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | FOCUS ON ALS 2018 is an important scientific event organized jointly between the Italian association for ALS (AISLA) and the Italian Foundation for the research on ALS (AriSLA). I gave the opening Plenary lecture |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.simposiosla.it/focus-on-als-2018/ |
Description | FutureNeuro Symposium, Dublin October 2018: Translating neurological research into clinical practice. Plenary lecture. A translational neuroscience approach to improve outcomes in ALS/MND: The journey so far and future prospects |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | The SFI FutureNeuro Center All Ireland Clinical Conference brought together neurologists from Ireland to build a common understanding of how Translational Research can be progressed in Ireland in the neurological field. This event aimed to build capacity in neurological science based on current research findings and to increase the knowledge level by presentation from international and domestic experts in the field. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.eventbrite.ie/e/futureneuro-all-ireland-clinical-conference-2018-tickets-48027266848# |
Description | John Mallet Purser Memorial Public Lecture 2023, Trinity College Dublin. November 2023. Motor Neuron Disease: a neurodegenerative disorder poised for successful therapy development. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I delivered a talk for a wide audience including Clinical Teaching Staff, Patient and Public contributors, Researchers, Retired Staff, Undergrad, Postgrad, Alumni, Faculty & Staff and the Public at Trinity College Dublin's annual John Mallet Purser public lecture on developments in therapy development for MND. |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.tcd.ie/news_events/events/event/john-mallet-purser-annual-lecture.php |
Description | Keynote lecture University of Leuven, Belgium May 2023 : Amyotrophic Lateral Sclerosis: a neurodegenerative disorder poised for successful therapy development. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | I delivered one of two keynote addresses for the launch of the Leuven Brain Institute ALS Centre, connecting eight clinical and research groups involved in ALS research at KU Leuven and UZ Leuven. I included highlights on SITraN's translational programmes; bringing NRF2 activator M102 towards first-in-man clinical trials supported by biomarkers, and developing an SRSF1 cell permeable peptide to inhibit the nuclear export and RAN translation of C9ORF72 repeat transcripts. |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.kuleuven.be/brain-institute/events-and-outreach/lbi-als-center-launch |
Description | Medical Research Council visit to the University of Sheffield July 2023. An overview of Neuroscience Research at the University of Sheffield |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | Gave an overview of neuroscience research at the University of Sheffield including highlighting the M102 programme under the translational neuroscience research pillar. |
Year(s) Of Engagement Activity | 2023 |
Description | My Name'5 Doddie Foundation Advisory Board presentation: Strategies for identification of new therapeutic targets for motor neuron disease. |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Delivered a talk to the charity My Name'5 Doddie Foundation scientific advisory board highlighting the complex pathophysiology of MND and developing therapeutic strategies including M102 targeting the NRF2 pathway and SRSF1 for C9ORF72-MND. I highlighted the importance of systematic biosampling in AMBRoSIA to deepen our understanding of the genetic foundations of MND and it's potential to help subclassify the disease and develop new therapeutic targets. The Foundation is planning a multi-million pound project to support target identification and validation for MND drug development in Spring 2024. |
Year(s) Of Engagement Activity | 2023 |
Description | Neurotherapeutics Symposium, Universities of Rochester and Florida, February 2018, Orlando USA. Understanding motor neuron disease: The path to treatment |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This symposium focuses on the process of testing new drugs for the management of neurologic diseases. It focuses on the fields of neuromuscular and movement disorders. One goal of the symposium is to support young investigators with mentoring opportunities. |
Year(s) Of Engagement Activity | 2018 |
URL | https://neurology.ufl.edu/2017/12/01/neurotherapeutics-symposium-2018/ |
Description | North of England Neurological Association (NENA), Harrogate, November 2023. NENA Plenary Opening Lecture. Motor Neuron Disease: a neurodegenerative disorder poised for successful therapy development. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | I delivered a talk of NENA, a forum for Neurologists, Neurosurgeons, Neurophysiologists, Neuropathologists, Neuroradiologists and Neuropsychologists to meet each autumn in order to discuss research, challenging cases and 'neurological life' in general. My talk highlighted developments in understanding the genetic foundation of MND, the importance of disease subclassification, biomarker development and systematic patient biosamples. I highlighted therapy development using M102, an NRF2 activator and targeting SRSF1 to prevent the nuclear export of C9ORF72 transcripts as examples. |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.nena.org.uk/ |
Description | Sorbonne University Paris virtual presentation April 2023. Amyotrophic Lateral Sclerosis: a neurodegenerative disorder poised for successful therapy development. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Gave a lecture for the Center of Research for Myology, a joint health research centre with the Faculty of Medicine of Sorbonne University and the INSERM (the only public research organization in France entirely dedicated to human health), for their new Monday Muscles Seminar series. My lecture on ALS and new therapeutic opportunities including biomarker development garnered enthusiastic feedback from the members of the Institute, especially the youngest postdocs and students. |
Year(s) Of Engagement Activity | 2023 |
URL | https://recherche-myologie.fr/event/monday-muscle-seminar-mms-pamela-shaw/?lang=en |
Description | Talk at the SITraN Open Day |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | A broad talk about mitochondrial drug screening in patient derived models of Parkinson's Disease. |
Year(s) Of Engagement Activity | 2017 |
Description | Target validation in ALS/MND meeting, London April 2018. The Nrf2-ARE pathway as a therapeutic target in ALS/MND |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | . |
Year(s) Of Engagement Activity | 2018 |
Description | The University of Sheffield Medical School Research Day: Uniting efforts for medical advances Collaboration and Knowledge Exchange |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation at a 2-day annual meeting showcasing the best research across the medical school to encourage and inspire junior researchers. I highlighted our systematic banks of patient biosamples through the AMBRoSIA project and the KE partnership with Aclispe to develop M102 including biomarker development through the CoEN programme and array of in vivo models with phenotypic readouts including the C9ORF72 transgeneic zebrafish model that attract industry KE partnerships for drug discovery and development. |
Year(s) Of Engagement Activity | 2023 |
Description | WELLCOME CONNECTING SCIENCE Molecular Neurodegeneration and Therapeutic Approaches |
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 | I delivered a component of a week long course aimed at individuals working in neurodegenerative research, neurogenetics or translational neuroscience (PhD students, clinical scientists, veterinary scientists, post-doctoral researchers and researchers based in the pharmaceutical and biotechnology industries). The pre-course reading material I specified to be circulated to attendees included our CoEN collaboration publication (https://www.sciencedirect.com/science/article/pii/S0891584921004214?via%3Dihub) and SRSF1 publication (https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-021-00475-y), delving into therapeutic translation for ALS. |
Year(s) Of Engagement Activity | 2024 |
URL | https://coursesandconferences.wellcomeconnectingscience.org/event/molecular-neurodegeneration-and-th... |
Description | Women Intrepreneurs |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Industry/Business |
Results and Impact | I had the opportunity to present my research activities in the field of neurodegeneration to a group of potential donors, all female business owners in the Yorkshire area. |
Year(s) Of Engagement Activity | 2019 |