Effective Sickle Cell Treatments

Sickle cell disease

Every year, 300,000 babies around the world are born with sickle cell disease (SCD).¹ SCD is an inherited blood disorder caused by mutated haemoglobin, a protein in red blood cells.² It is responsible for binding to and carrying oxygen, transporting it around the body to produce energy through metabolic processes. Abnormality of the haemoglobin protein causes several complications ranging from mild to severe, to potentially fatal. 

The life-long disease has affected the lives of approximately 20 million people around the world,³ the majority of whom are of African or Caribbean descent.⁴ Most alarmingly though, is that while 99% of children with SCD in the UK survive to adulthood, only a fraction ranging from 10–50% of those in Africa do as well.⁵ Given the striking contrast in life expectancy of children with SCD, timely, effective, and accessible treatment becomes central to tackling the blood disorder.

Bone marrow transplants have been the only cure for sickle cell disease since the 1980s. Even then, it is not carried out often due to significant health risks that vary from person to person.⁶ Hence, symptom management is the focus in the treatment of SCD for most people, if not all, to prolong life expectancy, reduce complications, and ultimately improve their quality of life. Nonetheless, there have been recent scientific developments in gene therapy, with Casgevy (exagamglogene autotemcel) being FDA-approved at the end of 2023.⁷ 

To what extent do these treatments prove to be both effective and accessible?

Aetiology 

Understanding the genetic basis of SCD facilitates our understanding of the mechanism of action of the treatments. As mentioned earlier, SCD is caused by a mutation in the haemoglobin gene. There is a point mutation where a Thymine (T) base replaces the Adenine (A) base at codon 6 of the ꞵ-haemoglobin chain⁸ hence, a valine amino acid is transcribed instead of glutamine amino acid when producing the haemoglobin protein.²

The mutated haemoglobin produced is referred to as haemoglobin S, known to cause red blood cells to become stiff when there is a low concentration of oxygen. While a normal red blood cell is round and has a disc shape, a sickled red blood cell stiffens to become hard, sticky, and has a C-shape. These characteristics of the sickled red blood cells are problematic as they are not flexible, causing blockages in the blood vessels.³ 

Symptoms

Pain episodes

Due to the blocked blood vessels, the reduced blood flow leads to a reduction in oxygen being supplied to tissue around the body. Tissue ischemia (lack of blood supply to the part of the body) may lead to inflammation, which can cause pain and occur in episodes called pain crises; it may also lead to pulmonary infarction – a fatal condition that occurs when lung tissue dies as a result of a lack of blood supply. 

Most concerningly, the blocked blood supply in the brain can cause an ischemic stroke, with children with SCD between the ages of 2 and 16 years at the highest risk in comparison to other age groups with SCD.⁹

Infections:

The blocked blood vessels in the spleen cause functional asplenia (spleen tissue does not work properly), leading to frequent infections, primarily bacterial. However, the spleen is not the only organ damaged as a result of blocked blood vessels:

1. Renal dysfunction (kidneys)
2. Retinopathy (eyes)
3. Increased risk of avascular necrosis (bones)¹⁰

Anaemia

The third main symptom is anaemia, a condition where the body does not have sufficient healthy red blood cells. In the case of SCD, there is a high level of abnormal red blood cells due to the mutated haemoglobin. Consequently, people with SCD may feel more fatigued, dizzy, and short of breath.¹¹ Finding a treatment that is effective for all people with SCD is fundamental for both reducing symptoms and improving overall health. 

Current treatment approaches

Fortunately, diagnosis is relatively simple; in addition to maternal screenings and ultrasounds, a blood test is conducted during newborn screening to diagnose sickle cell disease.¹² The difficult step following a positive result for the blood disorder is identifying a treatment that not only cures but is also safe. Whether it is for a newborn, an adult, or someone of European or African descent, the optimal treatment would work for all. 

Bone marrow transplantation

Though bone marrow transplantation remains the only cure for sickle cell disease, it fails to ensure safety for the majority of the population with SCD. In the early 2000s, a review evaluated the efficacy of bone marrow transplantation for sickle cell anaemia and where there was room for improvement. Needless to say, the procedure had an 85% disease-free survival rate and was established to be the only curative therapy.¹³

Haemopoietic stem cell transplantation

Similarly, haemopoietic stem cell transplantation for SCD can effectively prevent organ damage and repair previous organ dysfunctionality in most age demographics, particularly in the paediatric population.¹⁴ However, there are still many flaws to this technique:

• Limited number of suitable donors
• Invasive procedure
• Immunosuppression before surgery may increase the risk of infections
• Host body may reject the donor cells 
• Expensive¹⁵

Symptom management

Despite the multitude of health risks, there is still a possibility that the transplantation just doesn’t work. Therefore, a major component of treatment for SCD is symptom management. 

To reduce the occurrences and severity of pain crises, people with SCD are often prescribed hydroxyurea. Having been FDA-approved in 2017 for paediatric patients with SCD from the age of 2 years. Hydroxyurea is an antimetabolite that is most commonly used to treat cancer for its ability to slow down cancer cell growth. In SCD, hydroxyurea prevents red blood cells from hardening into their sickle shape by inhibiting the production of haemoglobin S.¹⁶

Instead, it increases the production of haemoglobin F, also known as foetal haemoglobin, as it is present in newborns. A nine-year study on the effects of hydroxyurea on SCD has shown that it significantly reduced mortality by 40%.¹⁷ While it can also improve pain crisis frequency and intensity, a patient may also be prescribed painkillers to reduce the intensity. 

For mild to moderate pain, codeine may be combined with acetaminophen or aspirin: for moderate to severe pain, morphine or hydromorphone may be prescribed.¹⁸

Given the high susceptibility to infections, penicillin is prescribed for daily use throughout the rest of an individual’s life as a preventative measure.

With regard to anaemia and strokes, blood transfusions are administered. For anaemia, there is a simple transfusion where the donor blood is injected into the patient without removing their blood; for strokes, an exchange transfusion is applied where the same occurs but the patient’s blood is removed either right before or during the transfusion.¹⁹ However, with both forms of transfusions, there is a risk of iron overload that can arise over time, putting the patient at risk of severe organ damage.

In summation, while there are remedies to the symptoms and even a cure, it is evident that there needs to be a single treatment capable of curing the disease as opposed to several treatments that ultimately have a negative impact on the burden of the disease.

Gene therapy

Gene therapy has the potential to solve this exact problem. In 2020, the inventors of Casgevy won a Nobel Prize, the first Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) therapy to treat sickle cell disease.²⁰ Contrary to bone marrow transplantation where the bone marrow of the patient is replaced with healthy stem cells from a donor, CRISPR involves editing the gene directly. Casgevy targets the BCL11A gene, which is associated with silencing the production of haemoglobin F.²¹

With higher levels of haemoglobin F, the production of haemoglobin S is delayed, and fewer red blood cells are sickled, reducing the possibility of anaemia. With fewer sickled red blood cells, there is a reduction in blood vessel blockages, reducing, and possibly eliminating, the frequency of pain crises and infections. While the prospects of Casgevy are promising, the NCT04208529 trial for its efficacy and safety is still ongoing and is expected to cover 15 years following treatment.²²

Summary

For decades, bone marrow transplant and a variety of therapies to manage symptoms was the only hope for people with SCD. While they are effective in their function, they still pose health risks that may outweigh the benefits. With gene therapy on the rise, there is a possibility for a treatment that overcomes the risks that come with rejection and immunosuppression.

Though it has made headlines in the scientific industry, it is still early days for Casgevy and we can only hope that, in the meantime, treatment can become more accessible and affordable for a wider population of people with SCD.