AbstractEndogenous metabolite levels describe the molecular phenotype that is most downstream from chemical exposure. Consequently, quantitative changes in metabolite levels have the potential to predict mode-of-action and adversity, with regulatory toxicology predicated on the latter. However, toxicity-related metabolic biomarker resources remain highly fragmented and incomplete. Although development of the S1500+ gene biomarker panel has accelerated the application of transcriptomics to toxicology, a similar initiative for metabolic biomarkers is lacking. Our aim was to define a publicly available metabolic biomarker panel, equivalent to S1500+, capable of predicting pathway perturbations and/or adverse outcomes. We conducted a systematic review of multiple toxicological resources, yielding 189 proposed metabolic biomarkers from existing assays (BASF, Bowes-44, and Tox21), 342 biomarkers from databases (Adverse Outcome Pathway Wiki, Comparative Toxicogenomics Database, QIAGEN Ingenuity Pathway Analysis, and Toxin and Toxin-Target Database), and 435 biomarkers from the literature. Evidence mapping across all 8 resources generated a panel of 722 metabolic biomarkers for toxicology (MTox700+), of which 462 (64%) are associated with molecular pathways and 575 (80%) with adverse outcomes. Comparing MTox700+ and S1500+ revealed that 418 (58%) metabolic biomarkers associate with pathways shared across both panels, with further metabolites mapping to unique pathways. Metabolite reference standards are commercially available for 646 (90%) of the panel metabolites, and assays exist for 578 (80%) of these biomarkers. This study has generated a publicly available metabolic biomarker panel for toxicology, which through its future laboratory deployment, is intended to help build foundational knowledge to support the generation of molecular mechanistic data for chemical hazard assessment.

01 Oct 2021·Regulatory Toxicology and PharmacologyQ4 · MEDICINE

Progress towards an OECD reporting framework for transcriptomics and metabolomics in regulatory toxicology

Q4 · MEDICINE

Article

Author: Caiment, Florian ; Moussa, Laura ; Yauk, Carole L ; Sachana, Magdalini ; Leonards, Pim E G ; O'Brien, Jason ; Carpi, Donatella ; Martin, Alberto ; Gant, Timothy W ; Chorley, Brian N ; Strauss, Volker ; Auerbach, Scott S ; Vaccari, Monica ; Bouhifd, Mounir ; Luijten, Mirjam ; Gribaldo, Laura ; Rudaz, Serge ; O'Donovan, Claire ; Corvi, Raffaella ; Colbourne, John ; Weber, Ralf J M ; Schmitz, Oliver ; Ebbels, Timothy M D ; Thomas, Russell S ; Ekman, Drew R ; Harrill, Joshua A ; Viant, Mark R ; Williams, Antony J ; Jones, Stephanie P ; Faulhammer, Frank ; Beger, Richard D ; Williams, Andrew ; Kende, Aniko ; Burgoon, Lyle ; Vijay, Vikrant ; Debrauwer, Laurent ; Leite, Sofia B ; Hilton, Gina M ; Lawson, Thomas N ; Whelan, Maurice ; Chen, Tao ; Sobanski, Tomasz

Omics methodologies are widely used in toxicological research to understand modes and mechanisms of toxicity. Increasingly, these methodologies are being applied to questions of regulatory interest such as molecular point-of-departure derivation and chemical grouping/read-across. Despite its value, widespread regulatory acceptance of omics data has not yet occurred. Barriers to the routine application of omics data in regulatory decision making have been: 1) lack of transparency for data processing methods used to convert raw data into an interpretable list of observations; and 2) lack of standardization in reporting to ensure that omics data, associated metadata and the methodologies used to generate results are available for review by stakeholders, including regulators. Thus, in 2017, the Organisation for Economic Co-operation and Development (OECD) Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST) launched a project to develop guidance for the reporting of omics data aimed at fostering further regulatory use. Here, we report on the ongoing development of the first formal reporting framework describing the processing and analysis of both transcriptomic and metabolomic data for regulatory toxicology. We introduce the modular structure, content, harmonization and strategy for trialling this reporting framework prior to its publication by the OECD.

Journal of Patient-Reported Outcomes

Development and usability testing of an electronic patient-reported outcome (ePRO) solution for patients with inflammatory diseases in an Advanced Therapy Medicinal Product (ATMP) basket trial

Article

Author: Wilson, Roger ; Mittal, Saloni ; Bathurst, Camilla ; Rowe, Anna ; Hunn, Amanda ; Malpass, Rebecca ; Retzer, Ameeta ; Harding, Rosie ; McNamara, Gary ; van Reil, Wilma ; Boyd, Alan ; Hughes, Sarah E ; Walker, Anita ; Kyte, Derek ; Calvert, Melanie ; McMullan, Christel ; Aiyegbusi, Olalekan Lee ; Price, Gary ; Dunster, Helen ; Davies, Elin Haf ; Denniston, Alastair K ; Frost, Chris ; Coleman, Jamie ; Mitchell, Sandra ; Newsome, Philip N

AbstractBackgroundElectronic patient-reported outcome (ePRO) systems are increasingly used in clinical trials to provide evidence of efficacy and tolerability of treatment from the patient perspective. The aim of this study is twofold: (1) to describe how we developed an electronic platform for patients to report their symptoms, and (2) to develop and undertake usability testing of an ePRO solution for use in a study of cell therapy seeking to provide early evidence of efficacy and tolerability of treatment and test the feasibility of the system for use in later phase studies.MethodsAn ePRO system was designed to be used in a single arm, multi-centre, phase II basket trial investigating the safety and activity of the use of ORBCEL-C™ in the treatment of patients with inflammatory conditions. ORBCEL-C™ is an enriched Mesenchymal Stromal Cells product isolated from human umbilical cord tissue using CD362+ cell selection. Usability testing sessions were conducted using cognitive interviews and the ‘Think Aloud’ method with patient advisory group members and Research Nurses to assess the usability of the system.ResultsNine patient partners and seven research nurses took part in one usability testing session. Measures of fatigue and health-related quality of life, the PRO-CTCAE™ and FACT-GP5 global tolerability question were included in the ePRO system. Alert notifications to the clinical team were triggered by PRO-CTCAE™ and FACT-GP5 scores. Patient participants liked the simplicity and responsiveness of the patient-facing app. Two patients were unable to complete the testing session, due to technical issues. Research Nurses suggested minor modifications to improve functionality and the layout of the clinician dashboard and the training materials.ConclusionBy testing the effectiveness, efficiency, and satisfaction of our novel ePRO system (PROmicsR), we learnt that most people with an inflammatory condition found it easy to report their symptoms using an app on their own device. Their experiences using the PROmicsR ePRO system within a trial environment will be further explored in our upcoming feasibility testing. Research nurses were also positive and found the clinical dashboard easy-to-use. Using ePROs in early phase trials is important in order to provide evidence of therapeutic responses and tolerability, increase the evidence based, and inform methodology development.Trial registration: ISRCTN, ISRCTN80103507. Registered 01 April 2022, https://www.isrctn.com/ISRCTN80103507

News (Medical) associated with University of Birmingham Enterprise Ltd.

15 Aug 2023

·www.prnewswire.com

Novel biologic Ab-IPL-IL-17™ shows promise for rheumatoid arthritis and inflammatory bowel disease

BIRMINGHAM, England, Aug. 15, 2023 /PRNewswire/ -- University of Birmingham Enterprise Ltd , 15 August 2023: Research has shown that a novel antibody generated to target an 'essential amino acid sequence' of both interleukin-17A and F has greater activity and potentially fewer side effects than existing biological therapies for conditions such as as rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease (IBD). Continue Reading Research published today reports the results of animal, cell and tissue studies that demonstrate the potential clinical benefit for people with rheumatoid arthritis and inflammatory bowel disease. The antibody, called Ab-IPL-IL-17™, targets a specific section of signalling proteins IL-17A and IL-17F which play a central role in sustaining inflammation during onset and progression of autoimmune diseases. A paper published today in the Annals of Rheumatic Diseases identifies the sequence, and reports the results of animal, cell and tissue studies that demonstrate the effectiveness of Ab-IPL-IL-17™, and its potential clinical benefit for people with RA and IBD. Authored by Dr Asif Iqbal from the University of Birmingham and Professor Francesco Maione, Head of ImmunoPharma Lab from the University of Naples Federico II, the paper reports studies which showed: Ab-IPL-IL-17™ displays potent anti-inflammatory activity in tissue and animal studies; Maintains this activity without triggering unwanted 'off target' effects seen with some currently available, less specific, antibody therapies; Reduces the pathological symptoms of arthritis and inflammatory bowel disease and is as effective as the current gold-standard treatment for RA at halting disease progression and triggering resolution. A patent application has been filed covering the antibody and its therapeutic use. The researchers are seeking commercial partners willing to conduct a large-scale clinical evaluation of Ab-IPL-IL17™ in patients with immune-mediated inflammatory diseases (IMIDs). The research demonstrated a short sequence of IL-17A and IL-17F is the most biologically active sequence of IL-17, stimulating the release of cyto-chemokines (inflammatory molecules that generate and amplify inflammation), to the same extent as full-length IL-17, and driving immune cell migration to an even greater extent than the parent molecule. Animal studies comparing Ab-IPL-IL-17™ to existing anti-IL-17 therapies (secukinumab, ixekizumab and bimekizumab) showed it does not trigger unwanted immune responses, reduce the numbers of platelets, or increase the numbers of lymphocytes (white blood cells) in the blood. For commercial enquiries contact Dr Veemal Bhowruth at University of Birmingham Enterprise. The University of Birmingham is ranked amongst the world's top 100 institutions, and its work brings people from across the world to Birmingham, including researchers and teachers and more than 6,500 international students from nearly 150 countries. Photo - SOURCE University of Birmingham Enterprise

Immunotherapy

100 Deals associated with University of Birmingham Enterprise Ltd.

100 Translational Medicine associated with University of Birmingham Enterprise Ltd.

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Ab-IPL-IL-17 ( IL-17A x IL-17F )	Rheumatoid Arthritis More	Preclinical

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