Page 16 - 2021_09-Haematologica-web

Ferrata Storti Foundation
Haematologica 2021 Volume 106(9):2304-2311
Towards manufactured red blood cells for the treatment of inherited anemia
Stephanie Pellegrin,1,2 Charlotte E. Severn1,2 and Ashley M. Toye1,2,3
1School of Biochemistry, Biomedical Sciences Building; 2National Institute for Health Research (NIHR) Blood and Transplant Research Unit in Red Blood Cell Products, University of Bristol and 3Bristol Institute of Transfusion Sciences, NHSBT Filton, Bristol, UK
ABSTRACT
Patients with inherited anemia and hemoglobinopathies (such as sick- le cell disease and β-thalassemia) are treated with red blood cell (RBC) transfusions to alleviate their symptoms. Some of these patients may have rare blood group types or go on to develop alloimmune reactions, which can make it difficult to source compatible blood in the donor population. Laboratory-grown RBC represent a particularly attrac- tive alternative which could satisfy an unmet clinical need. The challenge, however, is to produce - from a limited number of stem cells - the 2x1012 RBC required for a standard adult therapeutic dose. Encouraging progress has been made in RBC production from adult stem cells under good man- ufacturing practice. In 2011, the Douay group conducted a successful proof-of-principle mini-transfusion of autologous manufactured RBC in a single volunteer. In the UK, a trial is planned to assess whether manufac- tured RBC are equivalent to RBC produced naturally in donors, by testing an allogeneic mini-dose of laboratory-grown manufactured RBC in multi- ple volunteers. This review discusses recent progress in the erythroid cul- ture field as well as opportunities for further scaling up of manufactured RBC production for transfusion practice.
Introduction
Red blood cell (RBC) transfusions are the mainstay treatment for anemic patients and are given routinely in hospitals around the world. Depending on the clinical presentation, blood transfusions are likely to be administered to improve the patients’ quality of life and are administered either intermittently when needed, or for extended periods, as in the case of 50-90% of patients suffering from myelodys- plastic syndromes and for transfusion-dependent patients with inherited anemia and hemoglobinopathies (such as sickle cell disease and β-thalassemia). Chronic RBC transfusions introduce secondary complications which contribute to morbid- ity, due mainly to transfusion-induced iron overload and erythrocyte alloimmu- nization.1,2 It is particularly challenging for blood services to source RBC compatible for multiply alloimmunized patients with chronic transfusion-dependent anemia or rare blood types.3,4
Breakthroughs in the field of erythropoiesis research have led to the development of reproducible protocols that can yield large numbers of cultured human reticulo- cytes, often referred to as laboratory-grown or cultured red blood cells (cRBC). In addition to being an excellent model system for exploring human erythropoiesis in health and disease, this work has laid the foundations for the interest in producing human cRBC for transfusion purposes or as a vehicle for red cell-based therapeu- tics. The production of cRBC from stem cells or other cellular sources (see below) may one day fill the unmet clinical need for transfusion-dependent patients, but only if the challenge of growing enough clinical grade RBC can be met.
The term “manufactured RBC” (mRBC) refers to clinical grade cRBC grown under good manufacturing practises (GMP). Both cRBC and mRBC are in fact nascent RBC, known as reticulocytes5-7 and they are referred to only as mRBC within this manuscript from now on to avoid confusion. One added benefit of mRBC, com- pared to standard donor-derived RBC, is that they are a homogeneous population of immature RBC that should last the normal 120-day lifetime in the circulation. This
Correspondence:
ASHLEY TOYE
ash.m.toye@bristol.ac.uk
Received: February 2, 2021. Accepted: March 31, 2021. Pre-published: May 27, 2021.
https://doi.org/10.3324/haematol.2020.268847 ©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
2304
haematologica | 2021; 106(9)
REVIEW ARTICLE