How the approval of the first CRISPR gene therapy will change the treatment of sickle cell disease and beyond

Complications and management of sickle cell disease: a lifelong challenge

What is sickle cell disease?

Sickle cell disease is one of the most common hereditary diseases worldwide and the most prevalent blood disorder globally. The disease arises from a mutation in the haemoglobin gene, resulting in the production of abnormal, sickle-shaped red blood cells. These misshapen cells tend to clump together, blocking blood flow and causing a range of potentially life-threatening complications. Among the complications is anaemia, caused by the destruction of blood cells, leading to dizziness and fatigue. The so-called sickle crisis, also known as pain crisis, occurs when blood flow is blocked, leading to severe pain in the chest, arms, and legs. A life-threatening condition, stroke, may occur when brain vessels are blocked by sickled cells. Overall, all organs are repeatedly inadequately supplied with oxygen, leading to long-term damage. As a consequence, individuals affected by the disease have an average life expectancy of just over 40 years¹https://www.hopkinsmedicine.org/health/conditions-and-diseases/sickle-cell-disease.

Are there potential cures for sickle cell diseases?

Sickle cell disease is a lifelong condition, and its complications may not be entirely preventable. Current treatments focus on managing symptoms and preventing complications. Lifelong (pain) medication and blood transfusions help to handle anaemia, pain, and prevent strokes. Hydroxyurea, for example, is a palliative medication that can reduce the episodes of severe pain. The costs to manage sickle cell disease-associated complications for the US healthcare system accumulates to about 1.7 to 5.2 million US dollars per patient. The only potentially curative option for sickle cell disease patients, before the approval of Casgevy, was a bone marrow transplant. This complex treatment carries a significant risk of serious complications or even death, and is therefore offered only to patients with severe symptoms who have not responded to other treatments.

A paradigm shift in sickle cell disease treatment

Companies have started to exploit CRISPR technology to treat sickle cell disease

The newly approved CRISPR-based drug, Casgevy, is a one-time intravenous infusion for adults and children aged 12 years and older. It has the potential to cure sickle cell disease and is classified as an advanced therapy medicinal product (ATMP). ATMPs are innovative medicines based on gene therapy, cell therapy, or tissue engineering, offering new ways to treat diseases or medical conditions. Casgevy reactivates the production of fetal hemoglobin, which is produced during fetal development and is highly effective at carrying oxygen. Its production is switched off after birth and replaced by its adult counterpart, which, in sickle cell patients, is abnormally shaped and causes the complications mentioned above. For the treatment, stem cells are collected from the patient, similar to the process for a bone marrow donor. These cells are then edited using CRISPR to remove the genomic region that inhibits fetal haemoglobin production. Before the edited cells can be re-administered, patients must undergo preparatory chemotherapy to eliminate any remaining native stem cells in their bone marrow, creating space for the CRISPR-edited cells. Once administered, these CRISPR-edited cells can settle back into the bone marrow and produce fetal haemoglobin.

Recent clinical trials of CRISPR treatments for sickle cell disease are promising

By increasing the production of fetal haemoglobin, Casgevy helps to dilute the faulty sickle-shaped blood cells, thereby eliminating symptoms and improving overall health outcomes. Its efficacy was demonstrated in two ongoing, clinical trials involving patients aged 12 to 35 years. In one trial, 39 out of 42 patients remained transfusion-free for at least one year after Casgevy treatment. Simultaneously, in a second trial, 28 out of 29 patients were free of pain crises for at least 12 consecutive months²https://www.ema.europa.eu/en/news/first-gene-editing-therapy-treat-beta-thalassemia-and-severe-sickle-cell-disease.

The recent approval of Casgevy marks a groundbreaking shift, focusing on managing symptoms while addressing the underlying genetic cause. Although previous advancements have been made in improving patients’ quality of life, they have often fallen short in providing a complete and lasting solution.

3 challenges that need to be overcome to scale CRISPR-based treatments for sickle cell disease

Challenge n°1: make the CRISPR therapy accessible and affordable

While the approval of Casgevy represents a significant breakthrough, there are challenges that need to be addressed. Experts estimate that two million US dollars should be expected for the treatment of one patient. It remains to be seen, if insurance companies will be willing to cover the exceptionally high up-front costs for Casgevy. The high costs also remain a barrier to widespread access, especially in regions where most sickle cell patients reside. Around three-quarters of these patients are located in sub-Saharan Africa, where several million patients would be eligible for the new therapy, compared to a few thousand in the US and Europe. Governments of sub-Saharan African countries struggle to pay for basic health services, and patients often face difficulty in affording even 35 US dollars per month for basic (sickle cell) medications such as Hydroxyurea³https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756644/pdf/AJH-96-E2.pdf. Furthermore, the medical infrastructure required for such gene therapies exists in only a few countries worldwide. Therefore, several research groups, including Vertex Pharmaceuticals, are already working on cheaper and more accessible approaches to treat sickle cell patients globally. For instance, Intellia Therapeutics is developing treatments that perform CRISPR gene editing inside the body, which, once available, will reduce treatment costs.

Challenge n°2: ensure long-term effects

In addition to the challenge of high costs and accessibility, there is still a need to show the long-term safety of Casgevy (as test subjects in the approval studies have only been followed up for four years so far), and Vertex Pharmaceuticals has until August 2026 to submit the final results of the two ongoing clinical trials. In addition, treated patients will be followed up for 15 years to collect long-term data for an extended period and determine whether this therapy can also prevent the progression of chronic organ damage.

Challenge n°3: create suitable logistics for patients

Besides the costs and safety challenges, the necessity of undergoing chemotherapy and being hospitalized for months until the immune system recovers represents a further challenge for the patients. Despite all, hopes for Casgevy are high because the published data so far show no serious side effects observed in the first four years.

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A decade of progress and future horizons

Remarkably, these groundbreaking developments have unfolded within just a decade since the initial description of CRISPR by Jennifer A. Doudna and Emmanuelle Charpentier, and Casgevy will not remain the only approved CRISPR gene therapy. More companies are pursuing potentially curative therapies utilizing CRISPR-based treatments for various diseases, and some of these therapies may receive approval in the near future as well. For example, Excision BioTherapeutics is advancing its CRISPR-based therapeutic candidate, EBT-101, as a potential functional cure for chronic HIV infection. Intella Therapeutics is currently conducting a phase 3 study after showing promising data for their candidate NTLA-2001, a drug designed to treat patients with transthyretin amyloidosis with cardiomyopathy. The recent approval of Casgevy serves as just a glimpse into the possibilities of CRISPR gene therapy and the future of medical innovation.

The approval of Casgevy is a major breakthrough for the entire gene therapy field. The drug offers patients a new, effective treatment option and a potential cure that could improve their quality of life and life expectancy. The key to the success of CRISPR therapy is to drive down manufacturing costs so that it can be widely adopted and to demonstrate long-term safety and efficacy profiles. As research and development continue to advance, we at Alcimed look forward to an exciting future where CRISPR- based therapies offer a lifeline to millions of individuals affected by genetic, oncological or immunological diseases, providing them with the opportunity for a curative treatment. Alcimed follows the rapid developments in the field of biotherapeutics, and more specifically ofgene therapies and is happy to support you with your projects on these issues. Do not hesitate to contact our team!

About the author, 

Haiko, Consultant in Alcimed’s Life Sciences team in Germany