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Sickle Cell Disease: A 2024 Update

Over the last few months, including just in the last week, there have been multiple reports on new treatments for sickle cell disease. In this feature, we highlight the biggest updates in this field and think about what the future might hold.

What is sickle cell disease?

Sickle cell disease is a genetic blood disorder, characterised by defective haemoglobin in red blood cells. Haemoglobin is responsible for the transport of oxygen throughout the body, and the mutation responsible for the disorder leads to abnormal haemoglobin that causes the red blood cells to form a ‘sickle’ shape. These defective cells are prone to clumping together and can obstruct blood flow. This can result in what is known as vaso-occlusive events or crises – episodes of severe pain, and in in extreme cases, organ damage – as well as increasing the infection risk in patients.

The disease is inherited in an autosomal recessive manner. It stems from an A•T point mutation in the haemoglobin-beta gene (HBB), and predominantly affects those of African descent. The condition is relatively common – over 20 million individuals worldwide suffer from the disorder, with over 100,000 of these patients living in the USA. Sickle cell disease can be debilitating, leading to significantly decreased life expectancy, and medical needs have been historically unmet. Treatments thus far have targeted the symptoms of the disease, but these can be costly and invasive, such as stem cell transplants from healthy donors. However, of recent, new treatments have been making their way closer to the clinic.

Gene editing shows promise

In recent years, rapid technological advancements have meant that we can get to the bottom of, and potentially treat, the genetic defects responsible for some inherited conditions. Sickle cell disease is no exception. In fact, over the last couple of years, several potential therapies have been in the spotlight.

Different forms of gene editing have been trialled to correct the mutation over the years, and in 2021, base editing showed potential in mice. Gene editing pioneer David Liu was at the forefront of this research, which involved the use of an adenine base editor to switch the pathogenic thymine to a harmless cytosine. This tech improves upon CRISPR due to the fact it does not need to induce double-strand breaks to alter DNA. However, base editing still has limitations, and in experiments in both animal and cell models, the mutation could not be converted back to the wild type adenine.

Enter prime editing. Almost two years after the aforementioned work was published, in April 2023 Liu’s team showed that prime editing could restore the wild type HBB gene in cell models. This is because, unlike its predecessor, prime editing is not limited in the kind of base changes it can make. When edited stem cells were transplanted into mice with sickle cell disease, long-term function of the HBB gene was restored, with high clinical efficacy.

CRISPR makes its way into the clinic

Perhaps the biggest news in the genomics world last year was the approval of the first CRISPR-based gene therapy, which was designed to treat sickle cell disease and beta-thalassemia. Casgevy was approved in the UK and US in late-2023, and involves editing the patient’s haematopoietic stem cells to increase the production of foetal haemoglobin, which prevents the sickling of red blood cells. It does this by knocking out the regulatory elements that prevent the expression of foetal haemoglobin in mature cells, allowing for functional transport of oxygen around the body. The technique showed promise in clinical trials – some patients were free from vaso-occlusive events for months after administration – and didn’t require the identification of healthy donors, as the patient’s own cells could be used. The one-time treatment is also a vast improvement over the previous standard, which saw some patients needing monthly transplants.

In addition, a second gene therapy, Lyfgenia, was also approved in 2023. Lyfgenia uses a lentiviral vector to synthesise haemoglobin production in erythroid precursor cells. As with Casgevy, this drug showed promise in clinical trials.

The search continues

Although Casgevy was a breakthrough in sickle cell treatment, the therapy is still highly invasive. For example, patients require preparatory chemotherapy in advance of using the drug. In addition, there have been concerns over access to the treatment. Whilst the drug may significantly increase quality of life, it can cost millions to administer. As of March 2024, the decision had not yet been made to make Casgevy widely available on the NHS, as ‘further data on effectiveness’ was needed.

The quest for an effective treatment therefore continues. Just last week, researchers reported the development of an oral therapy that could be used to trigger the expression of foetal haemoglobin, similar to the fundamental mechanism behind Casgevy. This small molecule drug degrades a transcription factor, WIZ, which represses foetal haemoglobin in mature cells. In mice and non-human primates, the drug was well-tolerated, and the expression of foetal haemoglobin was significantly increased.

What does the future hold?

Whilst these treatments seem to hold promise, we’re still a long way from seeing them in the clinic. Even approved drugs like Casgevy are still the subject of accessibility issues, and so much still needs to be done to ensure that therapies are distributed in an equitable and affordable manner.

It may seem as though there is an abundance of news on sickle cell disease, but until recently the disorder had received relatively little research funding. It is well-documented that scientific research often focuses disproportionately on individuals of European descent. As such, blood disorders such as sickle cell and beta-thalassemia, which predominantly impact more diverse communities, have been often overlooked. Increased advocacy in recent years has catapulted sickle cell disease into the research sphere, but more still needs to be done. Ultimately, the disease’s relatively simple mechanism combined with the significant global health burden make it an effective target for researchers.

So, will we see more treatments for sickle cell disease being made available in the near future? The answer is almost certainly yes, and should these treatments show long-term positive results, it’s likely that the technology will drift into other areas too. For now, it’s vital that research continues, even in the wake of groundbreaking approvals, to ensure that the benefits can reach all who need them.


More on these topics

CRISPR / Gene Editing / Sickle Cell