In this article you will learn:
- What sickle cell disease and beta thalassaemia have in common at the level of haemoglobin
- How haematopoietic stem cells are collected, edited and returned to the patient
- Why conditioning chemotherapy is given before the edited cells are infused
- What the Casgevy studies measured in patients aged 12 to 35 years
- What happened to Zynteglo's EU authorisation and what that shows about the lifecycle of advanced therapies
- Which side effects are most common and which immune barriers scientists are still working on
- How to recognise an authorised advanced therapy and avoid unregulated offers
What are sickle cell disease and beta thalassaemia?
Sickle cell disease and beta thalassaemia are inherited blood disorders in which the body does not make enough normal haemoglobin – the protein in red blood cells that carries oxygen around the body[1]. In beta thalassaemia, patients do not make enough haemoglobin, so they have low red blood cell levels and need frequent blood transfusions[1].
In sickle cell disease, an abnormal form of haemoglobin makes red blood cells rigid and sticky, and changes their shape from a disc to a crescent – like a sickle[1]. These cells can block blood vessels and cause painful crises affecting the chest, abdomen and other parts of the body[1]. Both conditions are rare, and the active substances discussed here received orphan medicine designations for beta thalassaemia (17 October 2019) and sickle cell disease (9 January 2020)[1].
Treatment options for transfusion-dependent beta thalassaemia and severe sickle cell disease are limited[1].
Casgevy is licensed for beta thalassaemia only in patients who require regular blood transfusions[1]. For sickle cell disease, the licensed use is restricted to patients with severe disease and recurrent painful crises[1]. Both indications apply to patients 12 years and older[1].
Where do these medicines sit in EU regulation?
Advanced therapy medicinal products (ATMPs) are medicines for human use that are based on genes, tissues or cells, and they are classified into three main types[2]. The first type is gene therapy medicines, which contain genes that lead to a therapeutic, prophylactic or diagnostic effect[2]. The second is somatic-cell therapy medicines, which contain cells or tissues manipulated to change their biological characteristics[2]. The third is tissue-engineered medicines, where cells or tissues are modified to repair, regenerate or replace human tissue[2].
Gene-edited blood stem cell products belong to this ATMP framework[2]. Their clinical translation carries major biological, manufacturing and regulatory challenges, as is the case more broadly for cell therapies reaching the clinic[3]. Across the field of cell therapies more broadly, 28 cell therapy products have been approved globally and more than 1700 active clinical trials are under way, which shows how quickly this wider modality has grown[3].
Some ATMPs contain one or more medical devices as an integral part of the medicine, and these are referred to as combined ATMPs[2]. An example is cells embedded in a biodegradable matrix or scaffold[2]. In the EU, ATMPs are governed by Regulation 1394/2007 on advanced therapy medicinal products[2]. The cornerstone of that Regulation is that a marketing authorisation must be obtained before an ATMP is marketed[2]. All advanced therapy medicines are authorised centrally via the European Medicines Agency, which means a single evaluation and authorisation procedure[2]. EMA continues to monitor the safety and efficacy of advanced therapy medicines after they are approved and marketed[2].
In October 2017, the European Commission and EMA published a joint action plan on ATMPs[2]. The plan aims to streamline procedures and better address the specific requirements of ATMP developers[2]. In September 2022, EMA launched a pilot offering increased support to academic and non-profit organisations developing ATMPs[2]. The assistance included guidance throughout the regulatory process, from manufacturing best practice to clinical development and follow-up planning[2]. It also included fee reductions and waivers[2].
How does Casgevy work at the level of the stem cell?
Casgevy contains genetically modified stem cells – cells that can develop into blood cells – taken from the patient's own blood[1]. To make the medicine, these stem cells are edited using CRISPR/Cas9 technology so that they produce more fetal haemoglobin, a type of haemoglobin mainly found in babies in the womb but also present in small amounts in adults[1].
Because fetal haemoglobin can compensate for the lack of normal adult haemoglobin, the modified stem cells, when injected into patients, can raise red blood cell levels in beta thalassaemia and prevent painful crises in sickle cell disease[1]. CRISPR/Cas9 was adapted from bacteria for gene editing in human cells in 2012, and the first approval of a CRISPR-based medicine came 11 years later, for sickle cell disease and transfusion-dependent beta thalassaemia[4].
Casgevy is classified as an advanced therapy medicinal product, a category covering medicines based on genes, tissues or cells[6]. The approach relies on editing cells outside the body and returning them to the same patient, rather than on a conventional drug that acts inside the body[1].
How are the editing components delivered into the patient's cells?
Precise genome editing typically requires delivery of multiple components to the target cells, which may include messenger RNA, protein complexes and DNA fragments depending on the editing platform[5]. For clinical use, these components have to be delivered efficiently into transplantable cells, such as primary T lymphocytes or haematopoietic stem and progenitor cells, which are typically sensitive to exogenous substances[5].
Electroporation-based methods have generally been applied for gene editing, but procedure-associated toxicity has been a major burden[5]. Newer, less disruptive delivery methods now make it possible to deliver several components for precise editing safely and efficiently, expanding the applicability of these strategies[5]. Recent improvements aimed at cell specificity may enable in vivo targeting in the future[5].
Delivery systems for genome editing components fall into two broad groups: viral and non-viral systems[5]. Each group has its own advantages and limitations, and each has recent clinical applications[5]. The challenge of efficient delivery has limited the broad applicability of precise gene therapy to those strategies for which efficient delivery methods are available[5].
What does the treatment pathway look like for a patient?
Casgevy can only be obtained with a prescription and must be given in an approved centre by a doctor trained in giving this medicine and experienced in stem cell transplantation and in treating blood disorders affecting haemoglobin[1]. The medicine is made individually for each patient from stem cells collected from their blood and must only be given to the patient for whom it is made[1].
It is given as a single-dose infusion (drip) into a vein, and the dose depends on the patient's bodyweight[1]. Before Casgevy is given, the patient receives conditioning chemotherapy to clear the bone marrow of cells[1]. It is used when stem cell treatments are appropriate and no suitable stem cell donors are available[1].
The company that markets Casgevy will provide educational materials for healthcare professionals expected to use the medicine[1]. These materials cover its safety, including the potential risk of cancer and the need to monitor the patient's platelet levels, and how the medicine should be given[1]. Patients will also receive a guide and a card that they should carry with them[1]. Recommendations and precautions for healthcare professionals and patients are also included in the summary of product characteristics and the package leaflet[1].
What did the clinical studies measure, and in whom?
The effects of Casgevy are based on interim results of two studies that are still ongoing[1]. The studies did not compare Casgevy with another medicine or placebo. In one study, patients with thalassaemia aged between 12 and 35 years received the medicine after conditioning chemotherapy[1]. Of 42 patients, 39 maintained haemoglobin levels above 9 g/dL without needing blood transfusions for at least 12 consecutive months[1].
In a study in patients with severe sickle cell disease aged between 12 and 35 years, 28 out of 29 patients did not experience any painful crises for at least 12 consecutive months when treated with Casgevy after conditioning chemotherapy[1]. None of the patients (29 out of 29) required hospitalisation for painful crises for at least 12 consecutive months[1]. Because these are interim results from single-arm, uncontrolled studies, they describe outcomes in the treated patients rather than a comparison against standard care[1].
EMA noted that the studies with Casgevy were small and that there were uncertainties associated with their design[1]. Despite this, the studies showed that one-time treatment can reduce the need for red blood cell transfusions in beta thalassaemia and reduce the number of painful crises in sickle cell disease[1]. The company that markets Casgevy will provide results of ongoing studies to further assess the effectiveness and safety of the medicine[1].
How do the two haemoglobinopathy gene products differ in EU status?
| Product | Active substance | Approach | Indication in the EU | EU regulatory status |
|---|---|---|---|---|
| Casgevy | exagamglogene autotemcel | CRISPR/Cas9 editing of the patient's stem cells to raise fetal haemoglobin[1] | Beta thalassaemia requiring regular transfusions and severe sickle cell disease with recurrent painful crises, in patients 12 years and older[1] | Authorised for use in the European Union[1] |
| Zynteglo | betibeglogene autotemcel | – | Transfusion-dependent β-thalassaemia (at the time of authorisation)[6] | Withdrawn in the EU on 24 March 2022 at the request of the marketing authorisation holder, for commercial reasons[6] |
Zynteglo was granted a conditional EU marketing authorisation on 29 May 2019 for transfusion-dependent β-thalassaemia, initially valid for one year and renewed for additional one-year periods in 2020 and 2021[6]. The European Public Assessment Report for Zynteglo now indicates that the marketing authorisation is no longer valid[6].
Zynteglo's active substance was an autologous CD34+ cell enriched population containing haematopoietic stem cells transduced with a lentiviral vector encoding the βA-T87Q-globin gene[6]. At the time of authorisation, it was indicated for patients 12 years and older with transfusion-dependent β thalassaemia who do not have a β0/β0 genotype[6]. It applied where haematopoietic stem cell transplantation is appropriate but a human leukocyte antigen-matched related stem cell donor is not available[6]. Zynteglo had an accelerated assessment, meaning its review timeframe was 150 evaluation days rather than 210[6]. It was also classified as an advanced therapy medicinal product and received a conditional marketing authorisation[6]. The withdrawal was at the request of the marketing authorisation holder, bluebird bio (Netherlands) B.V., which notified the European Commission of its decision to permanently discontinue marketing for commercial reasons[6].
Casgevy received a conditional marketing authorisation valid throughout the EU on 9 February 2024[1]. Conditional authorisation is granted on the basis of less comprehensive data than are normally required[1]. It is granted for medicines that fulfil an unmet medical need to treat serious diseases, and when the benefits of having them available earlier outweigh any risks of using them while waiting for further evidence[1]. Every year, EMA will review any new information that becomes available until the data become comprehensive[1].
What are the known risks and the remaining scientific barriers?
The most common side effects with Casgevy, which may affect more than 1 in 10 people, include headache, nausea (sickness) and muscle and bone pain[1]. Doctors should consider whether patients can be given the required pre-treatments needed before Casgevy[1]. For the full list of side effects and restrictions, the package leaflet is the reference document[1].
Cell and gene therapies using haematopoietic stem cells have shown recent clinical successes for gene therapies involving autologous haematopoietic stem cell transplantation (HSCT)[7]. However, substantial immunological challenges remain: pre-existing immunity to gene-therapy reagents, immune responses to neoantigens introduced into stem cells by genetic engineering, and unique challenges associated with next-generation and off-the-shelf stem cell products[7].
CRISPR systems are also associated with unintended off-target and on-target alterations, including small indels and structural variations such as translocations, inversions and large deletions, which are a source of risk for patients[4]. A wide range of methods has been developed to detect unwanted effects of CRISPR-Cas nuclease activity, and these methods differ in their strengths and limitations[4]. The same review discusses how these detection strategies are relevant to preclinical risk assessment of CRISPR therapeutics in the current regulatory context[4].
In terms of safety, treatment with Casgevy was generally well tolerated, and side effects were mainly due to the conditioning chemotherapy[1]. There could be a theoretical risk of cancer caused by unintended changes in the genetic material, although no such cases have been seen so far[1]. There is also a potential risk of bleeding, since the medicine may cause a drop in the number of platelets, the components that help the blood to clot[1]. Measures are in place to monitor for such events through a 15 year registry-based study[1]. As for all medicines, data on the use of Casgevy are continuously monitored, and suspected side effects are carefully evaluated[1].
Recent advances in CRISPR gene-editing technologies, in the ex vivo expansion of haematopoietic stem cells and in non-genotoxic conditioning protocols are expected to significantly expand the range of clinical indications for stem cell-based gene therapies[7]. Addressing the immunological issues associated with current and next-generation stem cell gene therapies is seen as necessary to help realise the full potential of this field[7].
How can a patient tell an authorised advanced therapy from an unregulated one?
Unregulated advanced therapies may put patients at risk of serious side effects without proven benefits, and they are often sold on websites or through social media as a last hope, exploiting the worries of patients and their families[2]. Authorities are clamping down on suppliers of unregulated ATMPs and encourage patients and caregivers to report suspicious cases to their national authorities[2].
Watch for specific warning signs. Providers may market the product as experimental but use it outside an authorised clinical trial[2]. Providers may be unable to confirm that the product has been approved by EMA or by a national authority[2]. Claims of benefits may exceed those of approved treatments without supporting medical literature[2]. If a patient or family member has been offered an advanced therapy, contact the national competent authority to verify its approval[2]. Be cautious with treatments promoted online or through social media. Seek a second opinion before proceeding[2].
The EMA's Committee for Advanced Therapies and the Heads of Medicines Agencies issued a joint statement in March 2025[2]. It addresses the risks of unregulated advanced therapies. It also offers practical advice for patients and caregivers on how to identify them[2]. A similar statement from the Committee for Advanced Therapies was issued in April 2020[2].
The 2025 joint statement followed reports of providers offering unregulated dendritic cell therapies for cancer treatment in the EU[2]. A full list of EU national competent authorities is available from EMA for anyone who needs to verify a product or report a suspicion[2].
Where can patients look for ongoing research?
More than 1700 cell therapy trials are currently active globally, which means additional data on cell-based treatments continue to accumulate after a product is authorised[3]. Trials recruiting in Europe can also be searched on clinicaltrials.eu. Before joining any study, confirm with your treating centre that the trial is registered and authorised, and read the participant information carefully.
Cell therapies are currently one of the most investigated therapeutic modalities in both preclinical and clinical settings[3]. Many products have been approved and many more are under active clinical investigation[3]. Living cells can simultaneously and dynamically perform complex biological functions in ways that conventional drugs cannot, which is one reason the field has expanded the spectrum of available therapeutic options[3].
When to talk to your doctor or pharmacist
Ask your haematology team about gene-editing eligibility if you have transfusion-dependent beta thalassaemia or severe sickle cell disease with recurrent painful crises, and you are 12 years or older[1]. Discuss the conditioning chemotherapy step, because it clears the bone marrow before the edited cells are infused and doctors must consider whether pre-treatments can be given[1]. Report side effects such as headache, nausea, or muscle and bone pain to your treating centre, and read the package leaflet for the full list of side effects and restrictions[1]. If you are offered an advanced therapy outside an authorised trial or an approved centre, verify its approval with your national competent authority before proceeding[2].
Summary
Gene editing for sickle cell disease and beta thalassaemia is an ex vivo process[4]. A patient's own blood stem cells are collected and edited. In Casgevy, CRISPR/Cas9 is used to raise fetal haemoglobin. The edited cells are returned as a single intravenous infusion after conditioning chemotherapy[1]. Casgevy is authorised in the EU for patients aged 12 years and older[1]. It is indicated for transfusion-dependent beta thalassaemia or severe sickle cell disease. This authorisation is based on interim results from two ongoing, uncontrolled studies[1].
The history of Zynteglo shows that EU authorisation status can change: it was withdrawn in March 2022 at the holder's request for commercial reasons[6]. Verify approvals with your national competent authority, stay with approved centres and registered trials, and treat online offers of "experimental" cell therapies as a warning sign[2].
❓ What is Casgevy and who is it for?
Casgevy (exagamglogene autotemcel) is an EU-authorised medicine made from a patient's own genetically modified blood stem cells.1 It treats beta thalassaemia in patients who require regular blood transfusions and severe sickle cell disease with recurrent painful crises, in patients 12 years and older.1 It is used when stem cell treatments are appropriate and no suitable stem cell donors are available.1
❓ How does CRISPR editing raise fetal haemoglobin?
To make Casgevy, stem cells are edited with CRISPR/Cas9 so that they produce more fetal haemoglobin – a type of haemoglobin mainly found in babies in the womb but also present in small amounts in adults.1 Because fetal haemoglobin can compensate for the lack of normal adult haemoglobin, the modified cells can raise red blood cell levels in beta thalassaemia and prevent painful crises in sickle cell disease.1
❓ What results were seen in the Casgevy studies?
In a thalassaemia study in patients aged 12 to 35 years, 39 of 42 patients maintained haemoglobin levels above 9 g/dL without blood transfusions for at least 12 consecutive months after conditioning chemotherapy.1 In a severe sickle cell disease study in the same age range, 28 of 29 patients had no painful crises, and none required hospitalisation for painful crises for at least 12 consecutive months.1 These are interim results from ongoing studies without a comparator arm.1
❓ Why was Zynteglo withdrawn in the EU?
On 24 March 2022, the European Commission withdrew the marketing authorisation for Zynteglo (betibeglogene autotemcel) in the EU.3 The withdrawal was at the request of the marketing authorisation holder, bluebird bio (Netherlands) B.V., which notified the European Commission of its decision to permanently discontinue marketing for commercial reasons.3 The product had received conditional EU authorisation on 29 May 2019 for transfusion-dependent β-thalassaemia.3
❓ What are the most common side effects?
The most common side effects with Casgevy, which may affect more than 1 in 10 people, include headache, nausea (sickness), and muscle and bone pain.1 Doctors should also consider whether patients can receive the required pre-treatments needed before Casgevy.1 The package leaflet contains the full list of side effects and restrictions.1
❓ What other risks do scientists track in CRISPR therapies?
CRISPR systems are associated with unintended off-target and on-target alterations, including small indels and structural variations such as translocations, inversions and large deletions.8 These changes are a source of risk for patients and an important concern for developing safe therapies.8 A wide range of methods has been developed to detect unwanted effects of CRISPR-Cas nuclease activity, and these methods are discussed for their relevance to preclinical risk assessment.8
❓ What immune barriers remain for stem cell gene therapy?
Substantial immunological challenges remain for haematopoietic stem cell gene therapies, including pre-existing immunity to gene-therapy reagents and immune responses to neoantigens introduced into stem cells by genetic engineering.7 There are also unique challenges associated with next-generation and off-the-shelf stem cell products.7 With advances in CRISPR editing, ex vivo stem cell expansion and non-genotoxic conditioning protocols, the range of clinical indications for these therapies is expected to expand.7
- [1] Casgevy | European Medicines Agency (EMA) (accessed 02 June 2026) — https://www.ema.europa.eu/en/medicines/human/EPAR/casgevy
- [2] Advanced therapy medicinal products: Overview | European Medicines Agency (EMA) (accessed 02 June 2026) — https://www.ema.europa.eu/en/human-regulatory-overview/advanced-therapy-medicinal-products-overview
- [3] Cell therapies in the clinic. Europe PMC — https://europepmc.org/article/MED/34027097
- [4] Beyond the promise: evaluating and mitigating off-target effects in CRISPR gene editing for safer therapeutics. Europe PMC — https://europepmc.org/article/MED/38390600
- [5] Viral and Non-Viral Systems to Deliver Gene Therapeutics to Clinical Targets. Europe PMC — https://europepmc.org/article/MED/39000440
- [6] Zynteglo | European Medicines Agency (EMA) (accessed 02 June 2026) — https://www.ema.europa.eu/en/medicines/human/EPAR/zynteglo
- [7] Immunological barriers to haematopoietic stem cell gene therapy. Europe PMC — https://europepmc.org/article/MED/35301483
