Prevention of the complications of sickle cell disease in HbSC patients

Lead Research Organisation: University of Cambridge
Department Name: Veterinary Medicine

Abstract

Sickle cell disease (SCD) is a very common inherited condition with debilitating consequences. It results from the inheritance of an abnormal haemoglobin, the oxygen-carrying pigment of red blood cells. SCD patients have HbS, rather than the normal HbA, in their red cells. Patients may have only HbS (HbSS genotype) but other combinations are possible. The second most common is co-inheritance of HbS with a second abnormal Hb, HbC (HbSC genotype). In this case, patients? red cells contain equal amounts of HbS and HbC. HbSC disease represents about 1/3rd of the cases of SCD, with about 80,000 born annually worldwide. In all cases of SCD, red cell HbS aggregates into rigid rods when oxygen levels in the circulation are low, distorting red cell shape, making them sticky and fragile, thus reducing red cell longevity. It also encourages blockage of small blood vessels leading to organ damage and ultimately untimely death. A range of complications are seen: chronic anaemia plus symptoms of vascular occlusion (including stroke, damage to bone, retina, kidneys and lungs). This is true for HbSC individuals as well as HbSS ones. However, the disease in HbSC patients is significantly different with a different range of complications and different blood cell picture. This means that they should be considered as a discrete subset of SCD patients. Notwithstanding there is very little research pertaining specifically to HbSC patients. In fact, in most studies analysing the abnormal behaviour of red cells containing HbS and also clinical trials of potential new treatments, HbSC patients are specifically excluded. It is likely that the course of HbSC disease differs and that this results from a different abnormalities in the behaviour of their red cells. Central to this difference is the fact that the red cells contain both HbS and HbC. This work will study specifically HbSC patients. The behaviour of their red cells (containing both HbS and HbC) will be correlated with disease severity. Specific ways of stopping HbS polymerisation in HbSC red cells will be sought. Results will enable better management of HbSC patients and amelioration of the complications of SCD in this significant group of patients.

Technical Summary

Sickle cell disease (SCD) is one of the most common severe inherited disorders but specific treatments are lacking and the pathophysiology remains unclear. Approximately 250,000 SCD babies are born annually. Incidence in the UK amounts to around 12-15,000 individuals. Affected individuals have a mutated a globin gene resulting in the presence of an abnormal haemoglobin Hb, HbS, in their red blood cells. Whilst about two-thirds of SCD patients are homozygous HbSS individuals, patients heterozygous for HbS and a second Hb mutation HbC (ie HbSC heterozygotes) constitute about one-third of SCD cases, making HbSC disease the second most common form of SCD in UK and worldwide. In HbSC patients, red cells contain equal amounts of HbS and HbC. The complications of SCD are extensive, many resulting from the tendency of HbS to polymerise into long rigid rods on deoxygenation. Importantly, red cells from all SCD patients have an abnormal permeability, lose solutes and shrink, raising their total [Hb]. This markedly encourages HbS polymerisation. Patients? red cells have a reduced lifespan and are less able to traverse small blood vessels, causing chronic anaemia, microvascular occlusion and ischaemia affecting many organs. Although many symptoms are common to both, the condition is not identical in SCD patients of HbSS and HbSC genotypes. Disease complications and haematological findings differ. As such, HbSC disease should be treated as a discrete subset of SCD patients. Currently there is very little specific information on the pathophysiology and management of HbSC disease, with most knowledge being inferred from studies of HbSS. Differences in pathogenesis between HbSC and HbSS disease are expected. Understanding them will be important directly to the management of HbSC patients, and may also contribute to a better appreciation of HbSS disease. We hypothesise that the transport properties of red cells from HbSC patients differ significantly from those of HbSS individuals, accounting for the different symptoms observed of this group of patients, and enabling the design of unique therapeutic regimes to ameliorate HbSC disease. Preventing solute loss and deoxygenation-induced HbS polymerisation is more feasible in red cells from HbSC patients because their reduced content of HbS means that only a modest increase in cell hydration is required. We aim to understand solute loss in HbSC red cells in order to reduce ion permeability and thus achieve this greater degree of hydration.

Publications

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Gibson JS (2016) How benign is sickle cell trait? in EBioMedicine

 
Description BBSRC Studentship
Amount £60,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2010 
End 03/2014
 
Description Diagnosis and prognosis of sickle cell disease
Amount £47,000 (GBP)
Organisation Action Medical Research 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2010 
End 09/2011
 
Description Pathogenesis of HbS-Oman
Amount £209,000 (GBP)
Organisation Ministry of Health Sultanate of Oman 
Sector Public
Country Oman
Start 01/2015 
End 12/2018
 
Description PhD students funded by the Islamic Development Bank
Amount £120,000 (GBP)
Organisation Islamic Development Bank (IDB) 
Sector Private
Country Saudi Arabia
Start 01/2018 
End 12/2020
 
Description Project grant: Sickle cell disease and renal complications
Amount £91,290 (GBP)
Funding ID GN2030 
Organisation Action Medical Research 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 12/2014
 
Description Research project: Phosphatidylserine exposure in red blood cells from patients with sickle cell disease: calcium and oxidants
Amount £219,000 (GBP)
Funding ID 31966 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2016 
End 05/2019
 
Description Self-funded PhD studentship
Amount £143,562 (GBP)
Organisation Government of Taiwan 
Sector Public
Country Taiwan, Province of China
Start 10/2016 
End 09/2019
 
Description Sheik Jameel Studentship
Amount £120,000 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 12/2014
 
Description Studentship
Amount £212,000 (GBP)
Organisation Government of Kuwait 
Start 10/2017 
End 09/2021
 
Title Haemolytic assay 
Description Use of deoxygenated or low pH isosmotic non-electrolyyte solution for simpler diagnosis and potential prognosis of sickle cell disease 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact None as yet 
 
Title Proteomics for identification of Psickle 
Description Lysis material from red blood cells 
Type Of Material Biological samples 
Provided To Others? No  
Impact Attempt to identify Psickle, a key transport pathway implicated in the pathogenesis of sickle cell disease, whose molecular identity has not been established. Also identification of key regulatory enzymes in control of KCl cotransport activity. Finally, particular KCl cotransport isoforms involved in the disease 
 
Title Work with Professor David Rees, Paediatric Haematology, King's College London and King's College Hospital, London 
Description Using immortalised cell lines to study transport features of red cells, with CRISPR cas9 knockouts and knockins. 
Type Of Material Biological samples 
Year Produced 2018 
Provided To Others? No  
Impact Potential grant applications. Possible novel therapy for sickle cell disease. 
 
Description Altered regulation of cation cotransporter in sickle cells 
Organisation University of Edinburgh
Department Centre for Integrative Physiology
Country United Kingdom 
Sector Academic/University 
PI Contribution Novel assay for investigating cotransporter control in normal and sickle red cells
Collaborator Contribution Analysis of phosphorylated targets concerned with cotransporter regulation
Impact None but publication pending
Start Year 2013
 
Description Managing children with sickle cell nephropathy 
Organisation King's College Hospital NHS Foundation Trust (NCH)
Department Molecular Haematology
Country United Kingdom 
Sector Hospitals 
PI Contribution We are measuring prognostic indicators of red blood cell phenotype to predict development of renal disease in children
Collaborator Contribution Consent children and provide samples, analyse clinical data
Impact Publications
Start Year 2013
 
Description Pathogenesis of HbS-Oman 
Organisation Ministry of Health Sultanate of Oman
Country Oman 
Sector Public 
PI Contribution We will assess the phenotype of red cells and genotype of individuals of different subsets of patients with sickle cell disease in Oman
Collaborator Contribution This is just starting, but the aim is to identify prognostic measures and also potential therapeutic interventions. This population is poorly typed. Some have high levels of HbF but it is not known why - we hope to establish the cause.
Impact None as yet
Start Year 2015
 
Description Proteomics for identification of the deoxygenation-induced cation conductance of sickle cells 
Organisation King's College Hospital NHS Foundation Trust (NCH)
Department Molecular Haematology
Country United Kingdom 
Sector Hospitals 
PI Contribution Provision of samples and design of assay
Collaborator Contribution Establishment of proteomics matrix
Impact None
Start Year 2013
 
Description Work with Global Blood Therapeutics on new lef shift reagents from June 2017 
Organisation Global Blood Therapeutics
PI Contribution GBT440 is a new compound in phase 3 clinical trials in sickle cell patients. We have worked with GBT to look at a newer compound GBT1118, which may be more efficacious. It too increases oxygen affinity and reduces sickling, but we have shown that it also inhibits potassium permeability of red cells and better maintains hydration.
Collaborator Contribution Synthesised the new drug
Impact Manuscript in preparation.
Start Year 2017
 
Description American Red Cell Club Long Island, New York 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Conference of experts in red cell work including clinicians and research workers.
Year(s) Of Engagement Activity 2016
 
Description Charity fund raising 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Supporters
Results and Impact 50 people listened to invited talks about research funded by the charity

Interested feedback
Year(s) Of Engagement Activity 2012
 
Description Conference at Yale, New Haven, American Red Cell Club 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Discussion

Collaborations
Year(s) Of Engagement Activity 2015
 
Description Conference in Copenhagen, European Haematology Association 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussion and potential collaborations. Dissemination of information pertinent to care of patients with sickle cell disease

Clinical interest
Year(s) Of Engagement Activity 2015
 
Description European Society for Red Cell Research: Roscoff 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussion

Research collaborations
Year(s) Of Engagement Activity 2015
 
Description Presentation at the European School of Haematology Paris April 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation on red cell metabolism and diseases caused by enzyme deficiencies to train haematologists.
Year(s) Of Engagement Activity 2018
 
Description Presentation to year 12 students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact 25 school students attended and asked questions about role of red cells, oxygen delivery and sickle cell disease.

Encourage applications to Cambridge
Year(s) Of Engagement Activity 2013
 
Description Purdue University, USA. Talk to researchers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Discussion afterwards about novel therapies for sickle cell disease including targeted left shift reagents, with anion exchanger affinity to focus on red cells.

Interest from colleagues
Year(s) Of Engagement Activity 2014
 
Description Sickle cell conference KCH London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Audience of 250 healthcare workers including clinicians, nurses and research workers interested in care of sickle cell patients. Contributed to talk on biomarkers.

Interest in haemolysis test
Year(s) Of Engagement Activity 2013
 
Description Sickle cell conference at KCH London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact 200 delegates attended generating discussion about red cell problems in sickle cell disease

Email contact
Year(s) Of Engagement Activity 2010
 
Description Talk at Universitaat der Saarlandes in March 2018 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Outline the importance of studying membrane transport in red cells from sickle cell patients, as potential targets for novel chemotherapies
Year(s) Of Engagement Activity 2018
 
Description Talk at the Ameriican Red Cell Club in Cincinnati Childrens' Hospital October 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact About 100 clinicians and scientists attended. We outlined the importance of phosphatidylserine exposure in sickle cells and the role of oxidant damage.
Year(s) Of Engagement Activity 2017
 
Description Visit from year 12 school student 
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 Interest in science

School asked for pupils to attend my lab for work experience
Year(s) Of Engagement Activity 2015
 
Description Visit from year 12 school student 
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 Interest in career in science

School asked if GCSE pupils could visit my lab
Year(s) Of Engagement Activity 2014
 
Description Visit from year 13 school student 
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 Interest in applying to science courses at university

Stimulate application to university
Year(s) Of Engagement Activity 2015
 
Description Year 12 school student attended lab 
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 Introducing school student to biomedical research work on red cells.
Year(s) Of Engagement Activity 2016