Overview

Sickle Cell Anaemia is the most common and severe form of Sickle Cell Disease, a group of genetic red blood cell disorders, which are present at birth due to the inheritance of genes. Sickle cell anaemia poses as a painful condition that requires lifelong treatment. Multifactorial management treats Sickle cell anaemia. However, this leads to a treatment burden, and a cure is much needed. Gene therapy is a promising new modality which can rid the patient of painful symptoms for long time. Current gene therapy studies set precedence for the possibility of a cure with fewer risks.

Understanding sickle cell anaemia

In a healthy human body, our red blood cells carry oxygen with the help of a protein called ‘Haemoglobin’. Haemoglobin is an essential part of a red blood cell’s structure. As blood flows from arteries to capillaries, haemoglobin provides oxygen for all functions. 

However, a patient with Sickle Cell anaemia has red blood cells with faulty haemoglobin. This faulty haemoglobin turns a disk-shaped red blood cell into a sickle-shaped cell that is hard and prone to adhesion.¹ The changes in the characteristics of red blood cells lead to several complications such as, but not limited to:

1. Anaemia (lack of healthy red blood cells) due to the short lifespan of red blood cells
2. Painful episodes of sickle cell crisis/ vaso-occlusive crisis; adhesion of red blood cells causes occlusion of blood vessels
3. Increased susceptibility to severe infections due to impaired blood flow and chronic inflammation²

Though the specific presentation of symptoms can vary from case to case, generally, the patient experiences pain and fatigue, leading to a significant negative impact on the quality of life. To learn more about the symptoms, read further here.

Genetic basis

Sickle cell anaemia occurs due to the inheritance of an abnormal haemoglobin gene, the HbS gene.

Let’s dive deeper into what the HbS gene is.

The HbS gene is responsible for the abnormal haemoglobin S, which gives red blood cells their sickle shape and pathological characteristics in sickle cell anaemia. 

The HbS gene is inherited autosomal recessively. It means that two copies of the HbS gene cause complete expression of Sickle Cell Anaemia.³ The most common inheritance patterns of the HbS gene are as follows:

1. HbSS/ Sickle Cell Anaemia: inheritance of two copies of HbS gene, one from each parent
2. HbSC: inheritance of one HbS gene and one HbC gene; presents as Sickle Cell Disease, but not as severe as HbSS Sickle Cell Anaemia
3. HbAS/Carrier/ Sickle Cell Trait: inheritance of one HbS gene and one normal gene; patients may remain healthy carriers or have minor symptoms¹

Explanation of HbS gene mutation

The HbS gene is a result of genetic mutation. It occurs due to the change of a single nucleotide (building blocks of DNA) in the DNA sequence of the haemoglobin gene. The mutation occurs in populations where malaria is prevalent. The HbS gene provides some resistance to the disease.³

As the mutation silently travels down from generation to generation and spreads to different parts of the world through population migration, it becomes more common. According to The World Health Organization, around 5% of the world’s population are healthy carriers of the HbS gene trait.

So, what started as evolution’s attempt at strengthening humans against malaria has now become the cause of a painful disease worldwide. 

Management and traditional treatments

Due to its significant impact on the quality of life and a high mortality burden.⁴

The treatment guidelines focus on the following:

1. Screening and early diagnosis: Screening begins as early as pregnancy in high-risk mothers, and all babies are offered screening at birth. Blood tests can diagnose the disease at any age
2. Lifestyle changes: Patients should drink more fluids and eat healthy. They are advised to stay in warm places and avoid cold environments
3. Prevention of complications: There are medications to prevent the sickling of red blood cells, and to reduce the occurrence of painful sickle cell crisis. Hydroxyurea is a promising drug that prevents and reduces various complications. Prophylactic antibiotics and vaccinations are given to the patient to avoid severe infections
4. Pain management: Pain is a cause of concern in patients with sickle cell anaemia. Sometimes, over-the-counter painkillers are helpful, but in severe cases, doctors prescribe strong painkillers and even admit them for intravenous pain management
5. Other treatment depends on presenting symptoms: Patients with severe anaemia require folic acid supplements and blood transfusions^5,6

Currently, the only known cure for sickle cCell anaemia is stem cell/bone marrow transplant. However, this intensive treatment isn’t suitable for everyone and comes with many risks. Thus, the scientific world is looking for new modalities in the treatment that pose fewer risks and lower economic burdens. 

Gene therapy for sickle cell anaemia

Gene therapy is an emerging branch that has shown promising outcomes for treating Sickle Cell Anaemia. Gene therapy is defined as ‘the treatment of disease by transfer of genetic material into cells’.⁷ Since Sickle Cell Anaemia is an inherited disorder caused by defective genes, theoretically, gene therapy can be effective. 

Let’s break down the method of gene therapy in Sickle cell anaemia:

1. Patient’s cells, usually stem cells/bone marrow cells, are isolated
2. The DNA in the isolated stem cells produces functional haemoglobin
3. The patient goes through condition treatment. The patient is treated with chemotherapy to kill old cells in the bone marrow and make space for the new, altered cells
4. The altered cells are reintroduced to the patient’s body
5. Ideally, these altered stem cells will now produce red blood cells with functional haemoglobin and disk-shape⁸

Potential benefits and risks

The main benefit of gene therapy is that the patient gets treated with their stem cells. 

One of the main reasons stem cell/ bone marrow transplant is risky is due to the possibility of Graft-Versus-Host-Disease (GVHD). GVHD, is a common complication of donor stem cell transplant. It is a systemic disorder that occurs when the donor’s immune cells identify the recipient’s body as foreign, and start attacking the recipient’s cells. This complication can lead to complete failure of the transplant, systemic organ damage and even death. 

GVHD is avoided in gene therapy, since the stem cells are isolated from the patient’s body itself. Furthermore, it’s hard to find a match for stem cell donation. It is the reason why some patients would have to wait for a long time until they can find a donor. Meanwhile, they have todeal with the excruciating pain crisis. On the other hand, stem cells for gene therapy are readily available in the patient’s body.⁸

Gene therapy has risks. Chemotherapy used for condition treatment causes side effects such as nausea, loss of appetite, hair loss, mucositis and more. Most notably, it has a nearly 100% risk of infertility, which can be a cause of concern for young patients who may want to start a family later. Secondly, inserting the altered stem cells carries a long-term risk of developing secondary malignancy. Secondary malignancy can occur through two potential causes:

1. Patients with sickle cell anaemia are predisposed to chronic inflammation and damage to red blood cells, which can likely damage modified stem cells and cause malignant transformation
2. DNA alteration may damage the genome as well and cause malignant transformation

Gene therapy of Sickle Cell Anaemia is in an early stage of development. The risks and complications need more evaluation. 

Current gene therapy modalities

Currently, various studies are exploring the efficacy, risks and outcomes of gene therapy modalities for Sickle Cell Anaemia. 

One such ongoing study has evaluated the safety and efficacy of LentiGlobin. Initial results of the study showed reduced hemolysis (breakdown of red blood cells), production of functional HbA gene, and complete resolution of severe sickle cell crisis within the six months of follow-up. 3 out of 25 evaluable patients experienced reversible side effects, and no case of haematological cancer appearedat the time of analysis.⁹

In December 2023, Casgevy was approved by the MHRA (Medicines and Healthcare Products Regulatory Agency) of the United Kingdom. Casgevy is a gene therapy that uses minimal genome editing to achieve the production of functional haemoglobin. Clinical trial results showed that 28 out of 29 evaluable patients were free from sickle-anaemia related pain episodes for at least 12 months post-treatment, with no severe side effects noted at the time of analysis.¹⁰

Similarly, in December 2023, the U.S. Food and Drug Administration approved Lyfgenia gene therapy with Casgevy. Trials showed resolution of pain episodes within 6 to 18 months of follow-up in 88% of the patients. However, Lyfgenia gene therapy was associated with side effects and includes the occurrence of blood cancer as a warning in the label.¹¹

Future outlook

According to the National Heart, Lung, and Blood Institute (NHLBI), gene therapy is rising to the forefront of the discussion as a potentially curative or highly disease-modifying option for diminishing the complications of Sickle Cell anaemia.⁸

Sickle cell anaemiahas responded favourably to clinical trials and offers promising results. However, the trials are in their early phases and are evaluated on a small scale. Long term studies will help us assess the risks of gene therapy. 

Summary

Sickle Cell Anaemia is an inherited disorder of red blood cells that is characterised by persistent pain, and demands lifelong treatment. Gene therapy is a promising new treatment modality that focuses on correcting defective genes in the patient’s cells. Through clinical trials, gene therapy has shown complete resolution of painful symptoms of sickle cell anaemia for prolonged durations, and it is potentially curative.