Developing an initiative in stem cell editing for human genetic diseases.
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
The recent development of genome editing using programmable nucleases has already transformed our ability to perform experiments in mammalian cells rapidly, at high throughput and with high precision. The next challenge is to apply this discovery to precisely edit and correct genetic defects in human stem cells in a new approach to the treatment of inherited diseases. In this proposal we aim to address the key preclinical hurdles in achieving this by editing haematopoietic stem cells from patients with severe haemoglobinopathies, with the goal of rapidly progressing this knowledge to early phase clinical trials.
Using flexible funding allocated to the University as a block grant, we will facilitate the development of this new initiative bringing together the considerable expertise and technical know-how in a wide range of interdisciplinary groups to address this focussed problem. We anticipate that genome editing will ultimately find application in a wide range of human diseases and the University of Oxford is fully committed to support its early development in blood diseases to establish the principles of this approach and the longer term application of this exciting new technology to a broad range of challenges in clinical medicine.
Using flexible funding allocated to the University as a block grant, we will facilitate the development of this new initiative bringing together the considerable expertise and technical know-how in a wide range of interdisciplinary groups to address this focussed problem. We anticipate that genome editing will ultimately find application in a wide range of human diseases and the University of Oxford is fully committed to support its early development in blood diseases to establish the principles of this approach and the longer term application of this exciting new technology to a broad range of challenges in clinical medicine.
People |
ORCID iD |
Douglas Higgs (Principal Investigator) |
Publications
Adigbli G
(2021)
Development of LT-HSC-Reconstituted Non-Irradiated NBSGW Mice for the Study of Human Hematopoiesis In Vivo
in Frontiers in Immunology
Babbs C
(2020)
Variable cells with identical genetic codes.
in Blood
Badat M
(2023)
Direct correction of haemoglobin E ß-thalassaemia using base editors.
in Nature communications
Badat M
(2017)
Gene Therapy in a Patient with Sickle Cell Disease.
in The New England journal of medicine
Blobel GA
(2021)
Testing the super-enhancer concept.
in Nature reviews. Genetics
Broderick R
(2016)
EXD2 promotes homologous recombination by facilitating DNA end resection.
in Nature cell biology
Brown JM
(2018)
A tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions.
in Nature communications
Chiariello AM
(2020)
A Dynamic Folded Hairpin Conformation Is Associated with a-Globin Activation in Erythroid Cells.
in Cell reports
Dakin SG
(2018)
Chronic inflammation is a feature of Achilles tendinopathy and rupture.
in British journal of sports medicine
Dakin SG
(2017)
Increased 15-PGDH expression leads to dysregulated resolution responses in stromal cells from patients with chronic tendinopathy.
in Scientific reports
Engert A
(2016)
The European Hematology Association Roadmap for European Hematology Research: a consensus document.
in Haematologica
Francis H
(2020)
Scalable In Vitro Production of Defined Mouse Erythroblasts
Hay D
(2016)
Genetic dissection of the a-globin super-enhancer in vivo.
in Nature genetics
Hentges LD
(2022)
LanceOtron: a deep learning peak caller for genome sequencing experiments.
in Bioinformatics (Oxford, England)
Higgs DR
(2021)
Author Correction: Enhancer-promoter interactions and transcription.
in Nature genetics
Higgs DR
(2020)
Enhancer-promoter interactions and transcription.
in Nature genetics
Hua P
(2021)
Defining genome architecture at base-pair resolution.
in Nature
Jeziorska DM
(2022)
On-microscope staging of live cells reveals changes in the dynamics of transcriptional bursting during differentiation.
in Nature communications
King AJ
(2018)
Potential new approaches to the management of the Hb Bart's hydrops fetalis syndrome: the most severe form of a-thalassemia.
in Hematology. American Society of Hematology. Education Program
Larke MSC
(2021)
Enhancers predominantly regulate gene expression during differentiation via transcription initiation.
in Molecular cell
Long HK
(2020)
Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder.
in Cell stem cell
Lübbeke A
(2017)
The role of national registries in improving patient safety for hip and knee replacements.
in BMC musculoskeletal disorders
Mettananda S
(2018)
Molecular Basis and Genetic Modifiers of Thalassemia.
in Hematology/oncology clinics of North America
Mettananda S
(2017)
Selective silencing of a-globin by the histone demethylase inhibitor IOX1: a potentially new pathway for treatment of ß-thalassemia.
in Haematologica
Mettananda S
(2018)
Phenotypic and molecular characterization of a serum-free miniature erythroid differentiation system suitable for high-throughput screening and single-cell assays.
in Experimental hematology
Mettananda S
(2018)
Anaemia among females in child-bearing age: Relative contributions, effects and interactions of a- and ß-thalassaemia.
in PloS one
Mettananda S
(2017)
Editing an a-globin enhancer in primary human hematopoietic stem cells as a treatment for ß-thalassemia.
in Nature communications
Mettananda S
(2016)
Understanding a-globin gene regulation and implications for the treatment of ß-thalassemia.
in Annals of the New York Academy of Sciences
Miyata M
(2020)
An evolutionarily ancient mechanism for regulation of hemoglobin expression in vertebrate red cells.
in Blood
Oudelaar AM
(2018)
Single-allele chromatin interactions identify regulatory hubs in dynamic compartmentalized domains.
in Nature genetics
Oudelaar AM
(2017)
Robust detection of chromosomal interactions from small numbers of cells using low-input Capture-C.
in Nucleic acids research
Oudelaar AM
(2020)
Dynamics of the 4D genome during in vivo lineage specification and differentiation.
in Nature communications
Oudelaar AM
(2021)
The mouse alpha-globin cluster: a paradigm for studying genome regulation and organization.
in Current opinion in genetics & development
Snelling SJ
(2017)
Presence of IL-17 in synovial fluid identifies a potential inflammatory osteoarthritic phenotype.
in PloS one
Truch J
(2022)
The chromatin remodeller ATRX facilitates diverse nuclear processes, in a stochastic manner, in both heterochromatin and euchromatin.
in Nature communications
Wei W
(2019)
Germline selection shapes human mitochondrial DNA diversity.
in Science (New York, N.Y.)
Xiang G
(2020)
An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis.
in Genome research
Description | BRC3 Haematology and Stem Cell |
Amount | £4,602,645 (GBP) |
Funding ID | BRC3 |
Organisation | National Institute for Health Research |
Department | NIHR Biomedical Research Centre |
Sector | Public |
Country | United Kingdom |
Start | 04/2017 |
End | 03/2022 |
Description | Detection of mutations to allow safe gene editing and transplantation of haemopoietic cells |
Amount | £1,040,932 (GBP) |
Funding ID | MR/R008108/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2018 |
End | 02/2022 |
Description | Developing a programme for stem cell editing for human blood diseases |
Amount | £173,793 (GBP) |
Organisation | University of Oxford |
Department | John Fell Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2016 |
End | 12/2016 |
Description | Development of a novel therapy for beta thalassaemia using CRISPR/Cas9 to edit the major alpha globin enhancer |
Amount | £253,742 (GBP) |
Funding ID | MR/P019633/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2017 |
End | 09/2020 |
Description | Exploring mechanisms of enhancer action in erythropoiesis |
Amount | £250,000 (GBP) |
Funding ID | 209181 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2018 |
End | 03/2022 |
Description | Identifying suppressor mutations of ATR-X and ADNP syndromes using a novel CRISPR-based screening method in mice |
Amount | £250,000 (GBP) |
Funding ID | 210913 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2018 |
End | 10/2022 |
Description | The Oxford Single Cell Biology Consortium |
Amount | £399,179 (GBP) |
Funding ID | MR/M00919X/1 |
Organisation | University of Oxford |
Department | John Fell Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 05/2016 |
End | 03/2019 |
Description | WIMM - MRC Festival Establishment Award |
Amount | £3,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2019 |
End | 03/2024 |
Description | WIMM - WIMM MHU Capital Funding Award 2019/20 |
Amount | £85,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2019 |
End | 03/2020 |
Description | Enhancing tumour specific immune responses for the treatment of ovarian cancer |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Access to ovarian cancer biology and computational work |
Collaborator Contribution | Immunology expertise and cancer antigene prediction. |
Impact | The Ovarian Cancer Action (OCA) international grand challenge award Publication by Cancer Cell in Feb 2020: " The Repertoire of Serous Ovarian Cancer Non-genetic Heterogeneity Revealed by Single-Cell Sequencing of Normal Fallopian Tube Epithelial Cells" |
Start Year | 2016 |
Title | METHOD OF ANALYSING DNA SEQUENCES |
Description | The present invention relates to a method of identifying nucleic acid regions within a nucleic acid sample which interact with one another. In particular, the method relates to a chromatin conformation capture (3C) method which may be used to analyse the interactions between enhancers, silencers, boundary elements and promoters at individual loci at high resolution. |
IP Reference | WO2017068379 |
Protection | Patent application published |
Year Protection Granted | 2017 |
Licensed | No |
Impact | None so far |
Description | 11th Cooley's Anemia Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2022 |
Description | David & Jean Nathan Inaugural Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2022 |
Description | EBMT Haemoglobinopathy Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2022 |
Description | European School of Haematology |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2023 |
Description | MPI Berlin |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2023 |
Description | Molecular Haematology Unit seminar |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | A talk regarding the work on single-cell systems biology carried out by the company to date. This sparked a good debate between the presenter and the audience. |
Year(s) Of Engagement Activity | 2016,2017,2018,2019 |
Description | Oxford TEE meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2022 |
Description | Royal Society Summer Exhibition |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | The presentation was part of the Royal Society Summer Exhibition attended by schoolchildren, members of the public and members of the scientific community. This exhibition is probably the largest of the year in terms of attendees over the course of a week. |
Year(s) Of Engagement Activity | 2017 |
Description | Science Career Seminar |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | A career talk to students and post-docs involving working in the USA |
Year(s) Of Engagement Activity | 2016 |
Description | Spetses Summer School |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2022 |
Description | Switching Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2022 |
Description | Symposium on Chromatin Changes |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk in which I presented recent research from the laboratory following and introduction providing background to the field of interest. The attendance included students, junior research staff and senior scientists. |
Year(s) Of Engagement Activity | 2022 |