Repositioning histone modifying enzyme (HME) inhibitors as next-generation flukicides
Lead Research Organisation:
Aberystwyth University
Department Name: IBERS
Abstract
Fasciola hepatica is one of the aetiological trematodes of the global zoonotic disease, fascioliasis, which impacts agricultural, veterinary and medical systems on a global scale. Widespread use of the primary flukicide, triclabendazole (TCBZ) has led to developing anthelmintic resistance which threatens the security and sustainability of agricultural systems. Fascioliasis is now considered an emerging neglected disease and research efforts into novel therapies must urgently be prioritised. Histone modification enzymes (HMEs) have previously been targeted in anthelmintic development research, as studies in Schistosoma mansoni have demonstrated a targetable influence of these enzymes over parasite growth and development. This project aims to reposition HME inhibitors to determine their potential as novel flukicides. To achieve this, there are three main objectives:
1) Characterisation of the histone modification enzymes of Fasciola hepatica.
2) Validation of HMEs as potential targets for inhibitors.
3) Improvement of image analysis tools and AI models for motility and phenotype scoring in the juvenile stage.
1) Characterisation of the histone modification enzymes of Fasciola hepatica.
2) Validation of HMEs as potential targets for inhibitors.
3) Improvement of image analysis tools and AI models for motility and phenotype scoring in the juvenile stage.
People |
ORCID iD |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/T008776/1 | 30/09/2020 | 29/09/2028 | |||
| 2473651 | Studentship | BB/T008776/1 | 30/09/2020 | 29/09/2024 |
| Description | Discovery of three new lead compounds (potential new chemotherapies) against Fasciola hepatica by repositioning existing histone modification inhibitors (previously used in cancer research). Prioritisation of the inhibitor GSK-J4 as a lead compound for anthelmintic development. Development of deep-learning based parasite viability scoring models (split into segmentation and classification models) to improve objectivity of parasite scoring post drug treatment. This system will ultimately enable more high-throughput, quantifiable screening of compounds against Fasciola hepatica in the future. |
| Exploitation Route | Additional characterisations of the molecular and phenotypic effects of hit compounds not performed in thesis due to constraints of time, resources and funding (e.g. additional enzymatic, proteomic, transcriptomic/RNA-seq, RNAi experiments). Translational application of hit compounds to other closely related parasites (e.g. Fasciola gigantica, Calicophoron daubneyi) or distally related infectious organisms (e.g., protozoans). Modification of existing deep learning segmentation and phenotyping frameworks to include additional phenotypes (i.e., training with images from a wider range of compounds), imaging systems, parasites and life stages (e.g., Schistosoma mansoni, adult stage parasites etc.) Possibility to extend model to characterise stage development and measure parasite growth over time. |
| Sectors | Agriculture Food and Drink Digital/Communication/Information Technologies (including Software) Pharmaceuticals and Medical Biotechnology |
| Description | Spring Meeting Travel Award |
| Amount | £200 (GBP) |
| Organisation | British Society for Parasitology (BSP) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2022 |
| End | 03/2022 |
| Title | Deep learning segmentation and phenotyping models for Fasciola hepatica NEJs |
| Description | Early stages development of Python-based object segmentation and classification models for drug treated Fasciola hepatica newly excysted juveniles. Designed to work with Molecular Devices microscope systems but could be adapted to encompass additional systems. Works using mask-R-CNN based segmentation techniques in TensorFlow model garden and Xception-based classification in Keras. Training and optimisation of models performed over a year using pre-trained weights from Schistosoma mansoni models produced within the Hoffmann laboratory. Part of a collaboration with Informatics Unlimited (Cambridge). Aim is to further develop these basal models into an integrated software package with a GUI that will read images directly from a SQL database in house at Aberystwyth University. |
| Type Of Material | Computer model/algorithm |
| Year Produced | 2024 |
| Provided To Others? | No |
| Impact | Deployment of this model will allow quantitative parasite viability scoring based on phenotype that will reduce subjectivity of existing manual, categorical scoring system. Upscaling this model will increase reliability and accuracy of hit compound identification in F. hepatica, ultimately enabling high throughput drug screening and advancing the development of novel anthelmintics. |
| Description | IVL-11 as a flukicidal drug |
| Organisation | Ridgeway Research |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Ex vivo brightfield and fluorescence imaging (dextran, DAPI, phalloidin) of cultured Fasciola hepatica NEJs at 72 hours post compound treatment with IVL-11 (alpha hederin) and triclabendazole. Titrations of compounds for EC50 calculations in both IVL11 and TCBZ (24, 48 and 72 hours). Wet weight measurement of ex vivo fluke from animal trials using triclabendazole, closantel and IVL-11 (various concentraions) and statistical analysis of drug treatment impacts on fluke size and fecundity. |
| Collaborator Contribution | Investigation of the pharmacokinetics and efficacy of 5 saponin groups compounds in sheep. Modification of IVL-11 formulation to improve efficacy and tolerance. In silico compound modelling. Retesting of modified IVL-11 formulation in animal trials to determine maximal tolerated dose and comparability to triclabendazole and closantel. |
| Impact | Data pending publication (likely Phytotherapy Research). Multidisciplinary collaboration between in vitro animal scientists, compound chemists, parasitologists and computational biologists. |
| Start Year | 2022 |
| Description | Department Open Days |
| 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 | Undergraduate students |
| Results and Impact | Attended campus open days for prospective students and their parents on various weekends from 2020 - 2023. Provided facility and campus tours, demonstrations of practicals and general advice to applicants. |
| Year(s) Of Engagement Activity | 2020,2021,2022,2023 |
| Description | School Visit |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Delivered a careers fair stand at a secondary school to Year 8 students. Presented for parasitology as a specific career path, as well as encouraging students to pursue science more generally. The engagement involved presenting preserved parasites, allowing students to use microscopes to view fixed samples on slides, and demonstrating a prototype digital microscope built during my project. |
| Year(s) Of Engagement Activity | 2024 |