Our group is particularly interested in the genetics of red cell disorders. We use a range of genetic technologies to investigate the cause of the more commonly inherited anaemia, thalassaemia, and the rare inherited anaemias such as Congenital Dyserythropoietic Anaemia (CDA). In the long term, we hope that by combining state-of-the-art laboratory techniques with the Oxford clinical service, we will improve both diagnosis and treatments.
Our group also includes the national lead on studies of non-cancerous blood diseases, the NIHR Rare Diseases – Translational Research Collaboration website. (RD-TRC). The RD-TRC funds projects which investigate the physical characteristics and symptoms of rare genetic disorders. Current projects include work on inherited anaemias, Factor XI deficiency, inherited platelet disorders and paediatric (MDS) myelodysplastic syndromes.
CDA-1 is a very rare (one in a million) type of inherited anaemia. Patients range from requiring monthly blood transfusions to survive, to being tired and prone to absorbing excess iron from their diet. There is only one specific treatment for this condition, but not everyone responds to it and the side effects can be crippling. Only by understanding what goes wrong inside the cells can we come up with new treatments. In this photo is a red blood cell precursor from a patient with CDA-1- all of the little white holes should not be there. We have found some of the pieces of the puzzle to explain why that may be the case, but are missing some critical ones to complete the picture.
The Role of Iron Metabolism in Anaemia
Anaemia can also be caused by abnormalities in iron metabolism in the body. Our researchers in Prof Drakesmith's team are studying the molecular control of normal and abnormal iron metabolism, by focusing on the molecule hepcidin. In the last decade, hepcidin has emerged as the master regulatory hormone of iron metabolism. High levels of hepcidin inhibit iron absorption from the gut and inhibit the release of iron from storage cells, both of which decrease the amount of iron available for red blood cell production. This can contribute to anaemia and lead to a poor response to iron tablets. Our researchers are exploring whether measuring hepcidin levels in patients is a useful way to predict which patients will respond well to iron tablets. We would also like to find ways to decrease hepcidin levels, so that more iron is supplied to red blood cells, enabling a better recovery from anaemia.
ANAEMIA AND MYELODYSPLASTIC SYNDROME (MDS)
Professor Boultwood’s team investigates the molecular basis of Myelodysplastic Syndrome (MDS), a disorder affecting bone marrow cells. In patients with MDS, the production of all blood cell types is reduced, including red cells which leads to anaemia.
The team has previously shown that abnormalities in ribosomes (important protein factories in all cells) underlie the anaemia in the 5q-syndrome, a subtype of MDS. Prof. Boultwood and her team are currently studying what happens when drugs called translation enhancers (eg. L-leucine) and other drugs which have been shown to improve the anaemia in MDS (eg. ACE-536) with the aim to identify suitable MDS therapeutics.
Red cells research team
1. Clinical guidelines developed jointly with EHA and BSH for the commissioning of Next Generation Sequencing (NGS) for rare inherited anaemias. Noemi Roy led work across all GLHs (Genomic Laboratory Hubs), with a major role in designing, coordinating and delivering this change England-wide.
Turro E, Astle WJ, Megy K, Gräf S, Greene D, Shamardina O, Allen HL, Sanchis-Juan A, Frontini M, Thys C, Stephens J, Mapeta R, Burren OS, Downes K, Haimel M, Tuna S, Deevi SVV, Aitman TJ, Bennett DL, Calleja P, Carss K, Caulfield MJ, Chinnery PF, Dixon PH, Gale DP, James R, Koziell A, Laffan MA, Levine AP, Maher ER, Markus HS, Morales J, Morrell NW, Mumford AD, Ormondroyd E, Rankin S, Rendon A, Richardson S, Roberts I, Roy NBA, Saleem MA, Smith KGC, Stark H, Tan RYY, Themistocleous AC, Thrasher AJ, Watkins H, Webster AR, Wilkins MR, Williamson C, Whitworth J, Humphray S, Bentley DR; NIHR BioResource for the 100,000 Genomes Project, Kingston N, Walker N, Bradley JR, Ashford S, Penkett CJ, Freson K, Stirrups KE, Raymond FL, Ouwehand WH. Whole-genome sequencing of patients with rare diseases in a national health system. Nature. 2020 Jul;583(7814):96-102. doi: 10.1038/s41586-020-2434-2. Epub 2020 Jun 24. PMID: 32581362; PMCID: PMC7610553.
2. Oxford BRC work on use of and response to oral iron has fed into the development and award of NIHR-funded PGfAR including a multi-site clinical trial investigating the use of iron in preventing maternal anaemia to avoid fetal adverse outcomes. Sue Pavord led the development of UK guidelines for managing iron deficiency in pregnancy.
Pavord S, Daru J, Prasannan N, Robinson S, Stanworth S, Girling J; BSH Committee. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol. 2020 Mar;188(6):819-830. doi: 10.1111/bjh.16221. Epub 2019 Oct 2. PMID: 31578718.
3. Akshay Shah coordinated a feasibility study investigating Intravenous iron to Treat Anaemia following CriTical care (INTACT).
Shah A, Marian I, Dutton SJ, Barber VS, Griffith DM, McKechnie S, Chapman G, Robbins PA, Duncan Young J, Walsh T, Stanworth SJ. INtravenous iron to treat anaemia following CriTical care (INTACT): A protocol for a feasibility randomised controlled trial. J Intensive Care Soc. 2021 May;22(2):182. doi: 10.1177/17511437211012163. Epub 2021 May 3. PMID: 34025758; PMCID: PMC8120573.
Frost JN, Tan TK, Abbas M, Wideman SK, Bonadonna M, Stoffel NU, Wray K, Kronsteiner B, Smits G, Campagna DR, Duarte TL, Lopes JM, Shah A, Armitage AE, Arezes J, Lim PJ, Preston AE, Ahern D, Teh M, Naylor C, Salio M, Gileadi U, Andrews SC, Dunachie SJ, Zimmermann MB, van der Klis FRM, Cerundolo V, Bannard O, Draper SJ, Townsend ARM, Galy B, Fleming MD, Lewis MC, Drakesmith H. Hepcidin-Mediated Hypoferremia Disrupts Immune Responses to Vaccination and Infection. Med (N Y). 2021 Feb 12;2(2):164-179.e12.
Shah A, Frost JN, Aaron L, Donovan K, Drakesmith H; Collaborators. Systemic hypoferremia and severity of hypoxemic respiratory failure in COVID-19. Crit Care. 2020 Jun 9;24(1):320.
Richardson SL, Hulikova A, Proven M, Hipkiss R, Akanni M, Roy NBA, Swietach P. (2020) Single-cell O2 exchange imaging shows that cytoplasmic diffusion is a dominant barrier to efficient gas transport in red blood cells. Proc Natl Acad Sci U S A. 2020 Apr 22.
Roy NBA, Babbs C. The pathogenesis, diagnosis and management of congenital dyserythropoietic anaemia type I. Br J Haematol. 2019 May;185(3):436-449. doi: 10.1111/bjh.15817. Epub 2019 Mar 5. PMID: 30836435; PMCID: PMC6519365.