Sickle cell disorders are a group of inherited conditions affecting red blood cells, with sickle cell anaemia being the most severe form. This condition is more prevalent in people of African or Caribbean descent. Sickle-shaped cells have a shorter lifespan, leading to complications as they obstruct blood vessels. Though severe, the symptoms of sickle cell disease can be managed with various treatments.

Haematopoietic stem cell transplantation (HSCT) is currently the only curative option for sickle cell patients. There are two types: autologous, where a patient's modified stem cells correct the genetic mutation, and allogeneic, which uses healthy donor stem cells to replace defective ones. While HSCT can be curative, it carries significant risks and potentially fatal complications.

Overview of sickle cell anaemia

Sickle cell anaemia, as with all sickle cell disorders, is a collection of genetic disorders that impact haemoglobin, the primary protein in red blood cells responsible for oxygen transport. The typical red blood cells are disc-shaped and flexible enough to move easily through the blood vessels. The alteration in the shape of red blood cells is caused by a genetic mutation that occurs within the haemoglobin molecule in sickle cells. Sickle-shaped red blood cells are rigid and cannot bend or shape without obstructing the flow of healthy blood cells to other parts of the body.³

Symptoms of the condition include yellowish discolouration of the skin, known as jaundice, and/or yellowing of the whites of the eyes, known as icterus. These are due to the breaking down of large amounts of red blood cells, a process called haemolysis. When not enough healthy red blood cells and oxygen cannot be carried throughout the body, anaemia results, leading to extreme fatigue or fussiness. Other common symptoms include painful swelling of the hands and feet, referred to as dactylitis.³

What is a stem cell transplant?

Haematopoietic Peripheric Stem Cell Transplantation, often called bone marrow transplantation, involves administering healthy haematopoietic stem cells to patients with dysfunctional or depleted bone marrow. The procedure offers several advantages: it assists in increasing the functionality of the bone marrow. Additionally, it can allow the elimination of malignant tumour cells based on the nature of the actual disease being treated. In addition, the functional cells it produces replace dysfunctional cells in various diseases, such as immune deficiency syndromes and haemoglobinopathies.⁴

History and evolution

Haematopoietic progenitor stem cell transplantation began in the 1950s, inspired by mouse studies showing normal bone marrow could restore myelosuppressed marrow. This progress led to the first successful human bone marrow transplant between identical twins in New York in 1957, treating acute leukaemia. E. Donnell Thomas, who performed this procedure, continued his research and won the Nobel Prize for Physiology and Medicine. The first successful allogeneic transplant for severe combined immunodeficiency syndrome occurred in Minnesota in 1968.

Since then, allogeneic and autologous stem cell transplants have risen in the US and worldwide. Over 8000 allogeneic transplants were performed in the US in 2016, according to the CIBMTR, with an even more significant number of autologous transplants; autologous transplants have steadily outpaced allogeneic transplants over time.⁴

How stem cell transplants can help sickle cell patients

The process of getting a stem cell transplant

A bone marrow transplant or stem cell transplant is quite a lengthy procedure that starts with diagnostic tests to find out if the patient is fit enough for the treatment. The collection of stem cells is done by either the patient or a healthy donor by drawing blood, collecting bone marrow, or collecting cord blood. Conditioning treatment, which includes high doses of chemotherapy or radiotherapy, is collected to destroy the damaged bone marrow and suppress the immune system to make room for the new stem cells. Subsequently, the stem cells are introduced into the body through a painless, simple procedure.⁵

After the transplant, the patient remains in the hospital for several weeks while the new stem cells begin to generate healthy blood cells. During recovery, patients may experience side effects like fatigue, nausea, and a low blood cell count, requiring blood transfusions and careful monitoring. Since the immune system is weakened, there’s a heightened risk of infection, and some may need immunosuppressant drugs to prevent complications like graft-versus-host disease. Recovery can take months, with the immune system gradually regaining strength.⁵

Risks and challenges

A transplant of stem cells or bone marrow is a highly complex procedure with considerable risks, including serious complications like graft versus host disease (GvHD), in which the transplanted cells may attack the recipient's cells. Symptoms include an itchy rash, diarrhoea, and jaundice. Younger patients, usually those receiving transplants from closely matched siblings, generally run fewer risks. Following chemotherapy in preparation for the transplant, the blood cell count is reduced, leading to complications such as iron deficiency anaemia, bleeding, and increased infection risk. Many patients will need to stay in a germ-free hospital room. Side effects related to chemotherapy include nausea, diarrhoea, loss of appetite, and hair loss. Most of these symptoms are temporary, but there are several long-term effects associated with high-dose chemotherapy, such as permanent infertility. It also does not forget that discussing potential risks and benefits in advance with healthcare teams and families is essential.⁵

New developments in stem cell transplants

Since its conceptualisation and subsequent development, the advancement of stem cell therapy has raised hopes for curing diseases that had hitherto been considered incurable. Therapeutically, the application of stem cells emanates from their inherent ability to regenerate into the original tissues of the body. Secondly, stem cells can be engineered to deliver potent drugs or nanomaterials capable of immune modulation. Further innovative advances are also proceeding in immunotherapy with allogeneic cells and their move toward the clinic. The discipline of T cell immunology has focused on cytotoxic T lymphocytes, which have been demonstrated to be crucial in the immune defence against viral infections and malignancies. Currently, very few therapies involving the use of stem cells have been approved and incorporated into routine clinical practice.⁶

The most widely adopted form of stem cell therapy is the transplantation of haematopoietic stem cells to treat malignancies and disorders of the immune system and blood. Other clinical trials currently underway using stem cell therapies have, in some instances, generated impressive results, such as when iPSCs generated from patients upon induction to differentiate into pigment epithelial cells of the retina upon transplantation into subjects suffering from macular degeneration - a disease that greatly impairs the sight - and thus the patient's sight was greatly improved. More recently, iPSC-derived mesenchymal stromal cells have been, in a world-first, used to treat steroid-resistant graft vs. host disease.⁶

The future of stem cell transplants for sickle cell anaemia

The traditional treatments for sickle cell anaemia are the use of hydroxyurea, also known as hydroxycarbamide, to alleviate pain and prevent complications, as well as blood transfusions to increase the number of healthy RBCs. Despite this, the significantly traditional treatments are not always effective and they are accompanied by side effects; as a result, new treatment avenues are being constantly explored. Since 2015, the FDA has approved three SCD drugs with different modes of action; the list includes voxelotor, crizanlizumab, and L-glutamine. Researchers are looking into a regimen that can restore damaged cells through stem cell therapy while enhancing the bone marrow function of patients. Curative research has also focused recently on gene therapy, a technique that is meant to correct the genetic defect causing the disorder.⁷

Summary

Sickle cell anaemia treatment has no easy solutions, and safety still remains the top priority, while a bone marrow transplant emerges as a potential pathway of treatment for people living with sickle cell anaemia. However, there are certain risks that cannot be ignored, such as graft-versus-host disease, and longer recovery years are probable. Despite these difficulties, the continuous studies into stem cell treatments and the progress in gene therapy allow for the emergence of improved therapies. To ensure that these potentially revolutionary therapies have a fair chance of reaching all patients, directed actions should continue to ease access and improve treatments. By primarily focusing on research and reducing the inequalities in health care, we can work towards making stem cell transplantation one of the first-line options for sickle cell patients.