Garden Experts Insights | Gene Therapy in Thalassemia and SCD: UK Practice – Prof. De La Fuente

Gene Therapy in Thalassemia and Sickle Cell Disease: From Clinical Trials to Real-World UK Practice

Dr Josu de la Fuente
PhD FRCP FRCPI FRCPCH FRCPath
Consultant Paediatric Haematologist – Harley Street Paediatric Group London

This article is part of the GARDEN Experts Insights series, featuring key perspectives from leading international experts who contribute to GARDEN educational initiatives and webinars.In this edition, Dr. Josu de la Fuente explores the transition of gene therapy for severe haemoglobinopathies from clinical trials to real-world practice. Drawing on the UK experience, he examines the complex pathway surrounding treatment, from patient selection and clinical assessment to stem cell mobilization, apheresis, fertility considerations, conditioning, and long-term follow-up, highlighting the multidisciplinary expertise and infrastructure required to safely integrate gene therapy into routine care.

Introduction

Gene therapy has moved from an experimental concept to a clinical reality for people living with severe haemoglobinopathies. The development of autologous gene therapies and gene editing has created the possibility of long-term transfusion independence in transfusion-dependent beta thalassemia and sustained freedom from vaso-occlusive crises in severe sickle cell disease. Yet the transition from clinical trial to routine care changes the question. Clinical trials establish whether a therapy can work under carefully controlled conditions.

Real-world practice must determine whether an individual patient can safely reach treatment, tolerate stem cell mobilization and myeloablative conditioning, undergo successful manufacturing and reinfusion, and remain suitable for long-term follow-up. This distinction is central to the UK experience presented by Josu de la Fuente.

The webinar focuses on the practical pathway surrounding gene therapy, including patient selection, liver assessment, mobilization, apheresis, fertility, institutional infrastructure and multidisciplinary decision-making. These considerations are increasingly important as exagamglogene autotemcel, or exa-cel, becomes available through the NHS for selected patients with transfusion-dependent beta thalassemia and severe sickle cell disease.

From promise to practice

For decades, treatment of transfusion-dependent beta thalassemia depended on regular red cell transfusions combined with iron chelation. These interventions can substantially improve survival, but they do not correct the underlying genetic defect.

Chronic transfusion exposure also creates a cumulative iron burden, particularly in the liver and heart, requiring lifelong monitoring and chelation.
Sickle cell disease presents a different clinical burden. Hydroxycarbamide, transfusion programs and supportive care can reduce complications, but recurrent vaso-occlusive crises, acute chest syndrome, stroke and progressive organ damage remain major causes of morbidity.

Allogeneic hematopoietic stem cell transplantation has provided a curative option for selected patients, but the requirement for a suitable donor and the risks of graft-versus-host disease, graft failure and transplant-related complications have restricted its use. The attraction of autologous gene therapy is therefore clear. Instead of replacing the patient’s hematopoietic system with donor cells, the patient’s own stem cells are collected, genetically modified outside the body and subsequently returned after conditioning. This avoids donor matching and the immunological complications associated with an allogeneic graft.

The clinical evidence supporting this approach is now substantial. In the phase 3 CLIMB THAL-111 study, 32 of 35 evaluable patients with transfusion-dependent beta thalassemia achieved transfusion independence for at least 12 consecutive months after exa-cel, corresponding to 91%. Mean total hemoglobin during transfusion independence was 13.1 g/dL and mean fetal hemoglobin was 11.9 g/dL.

Importantly, fetal hemoglobin was distributed across at least 94% of red cells, suggesting broad correction of erythropoiesis rather than a small population of highly productive cells. The corresponding CLIMB SCD-121 study produced similarly striking results in severe sickle cell disease. Among 30 patients evaluable for the primary endpoint, 29, or 97%, remained free from severe vaso-occlusive crises for at least 12 consecutive months. All 30 patients were free from hospitalization for severe vaso-occlusive crises for at least 12 months. These results explain why gene therapy has reached clinical practice. But they do not mean that every patient with thalassemia or sickle cell disease is automatically a candidate.

Selecting the Patient

Patient selection is arguably the most important difference between a clinical trial and real-world gene therapy. The webinar highlights several patient-related barriers. Some individuals may have a strong desire to receive gene therapy but still fall outside current eligibility criteria because of age, organ damage, inadequate iron control or other clinical considerations.

This creates an important tension. The patients who have accumulated the greatest disease burden may also be those for whom intensive conditioning is least safe.
For transfusion-dependent beta thalassemia, the consequences of long-term disease are particularly relevant.

Repeated transfusions cause iron accumulation, while ineffective erythropoiesis contributes to abnormal iron regulation. Although modern chelation has significantly improved outcomes, longstanding iron overload can result in hepatic fibrosis, cirrhosis, cardiac iron deposition and endocrine complications.

The eligibility pathway therefore cannot be based solely on the diagnosis or transfusion requirement. It requires a broader assessment of organ reserve, iron burden, previous treatment, transfusion history, psychosocial circumstances and the patient’s ability to complete a complex treatment pathway.

This is also important in sickle cell disease. Gene therapy is not simply a treatment that can be administered during an ordinary outpatient visit. Patients must undergo mobilization, apheresis, manufacturing, conditioning and transplantation-like inpatient care.  The clinical benefit must therefore be balanced against the immediate toxicity of the treatment and the patient’s existing organ damage.

The distinction between biological eligibility and practical eligibility becomes particularly important in real-world medicine.  A patient may theoretically benefit from gene therapy but still require optimization before treatment. This is not a failure of the therapy. It is a consequence of applying an intensive cellular treatment to patients who have lived with chronic disease for many years.

Liver matters

The liver is particularly important in transfusion-dependent beta thalassemia because it is the principal site of iron accumulation. Chronic hepatic iron exposure can cause inflammation and fibrosis, while pre-existing liver disease may increase the risks associated with intensive conditioning.

The presentation describes a structured assessment incorporating liver function, ultrasound, liver stiffness measurement and liver iron concentration. Advanced liver disease is flagged by abnormalities such as marked elevation of transaminases, conjugated bilirubin or INR, together with structural abnormalities on imaging. For patients with significant liver iron overload, treatment may need to be delayed while iron chelation is intensified.

The webinar uses an 8 kPa liver stiffness measurement threshold as an important decision point. Patients with liver stiffness above this level are not immediately considered suitable and may require further investigation. Where liver stiffness is below 8 kPa, liver iron concentration becomes an important determinant.

Patients with liver iron concentration above 7 mg/g dry weight may require intensified chelation, while very high levels may lead to deferral until iron burden improves.
These criteria illustrate an important principle. Gene therapy does not remove the consequences of previous disease overnight.  A patient entering treatment carries the biological history of years of transfusion, iron exposure and chronic hemolysis.

Modern thalassemia guidelines similarly emphasize serial ferritin and magnetic resonance assessment of hepatic and cardiac iron. MRI-based liver iron concentration is now a central tool for assessing trans fusional iron burden, while cardiac T2 provides information about myocardial iron that cannot be inferred reliably from liver measurements alone.

Recent evidence also suggests that successful gene therapy can alter iron physiology after transfusion independence. In longer-term CLIMB follow-up, 55 of 56 patients had achieved at least 12 months of transfusion independence by April 2025, and 38 patients had discontinued iron removal therapy. Changes in erythroferrone and hepcidin suggested correction of ineffective erythropoiesis and restoration of iron homeostasis.

Mobilizing Stem Cells

Before gene therapy can occur, sufficient hematopoietic stem and progenitor cells must be collected. This is a technically demanding stage that is sometimes underestimated when gene therapy is described as a one-time treatment. In reality, the treatment begins weeks before the gene-modified cells are infused.

The webinar describes a mobilization and apheresis strategy involving G-CSF and plerixafor for thalassemia, with repeated collection when necessary. The target presented for thalassemia was approximately 3 to 15 × 10⁶ CD34-positive cells/kg on the first two collection days, with a potential third day for backup collection.

The real-world data presented shows that the number of mobilization cycles can vary considerably. In the full analysis set of 56 thalassemia patients, the median number of mobilization cycles was one, with a range from one to four. For 46 sickle cell patients, the median was two cycles, with a range from one to six. These figures illustrate an important practical distinction between the two diseases.

The webinar describes plerixafor administration before planned apheresis, with repeated dosing over the collection period. The goal is not simply to collect any stem cells, but to achieve a sufficiently large and high-quality CD34-positive cell product for manufacturing while minimizing the number of collection procedures.

Apheresis counts

Apheresis is another point at which the promise of gene therapy encounters practical reality. The patient’s stem cells must be collected in sufficient numbers to manufacture the final therapeutic product. The webinar presents specific collection targets and blood-volume processing requirements, reflecting the intensity of the procedure.

For thalassemia, the presentation describes processing approximately 4.5 total blood volumes on each of the first two collection days and approximately three total blood volumes on a potential third day. For sickle cell disease, the collection strategy similarly requires careful planning around mobilization, vascular access and the patient’s clinical condition.

The importance of these details is easy to miss when focusing only on clinical efficacy. A therapy can achieve impressive results in a phase 3 trial, but successful implementation requires a coordinated chain extending from eligibility assessment to stem cell collection, manufacturing, conditioning, infusion and follow-up.

The Conditioning Challenge

The genetically modified cells need space within the bone marrow niche to engraft. This is achieved through myeloablative conditioning, and current exa-cel protocols use pharmacokinetically guided busulfan. Conditioning is one of the most important limitations of current gene therapy. The genetic modification itself is not the only source of toxicity.

Much of the immediate treatment burden comes from the chemotherapy required before the modified cells are infused. Patients can experience prolonged cytopenias, infection risk, mucosal toxicity, liver complications and other effects associated with myeloablation. This creates a paradox in the current generation of gene therapy.

The therapeutic concept is highly precise, but the conditioning process remains relatively nonspecific. The CLIMB THAL-111 trial provides a useful illustration. All 52 patients receiving exa-cel in the prespecified interim analysis successfully achieved neutrophil and platelet engraftment. Nevertheless, the overall treatment pathway involved prolonged hospital-based care and monitoring consistent with autologous transplantation.

This is also why patients with advanced organ disease may be unsuitable. The same conditioning intensity that facilitates robust engraftment may create unacceptable risk in someone with significant hepatic, cardiac or other end-organ dysfunction.
Future conditioning strategies may therefore be as important as improvements in gene editing itself.

Antibody-based approaches designed to selectively clear hematopoietic stem cells without conventional chemotherapy are being investigated, with the aim of retaining effective engraftment while reducing infertility, mucosal injury, hepatic toxicity and other complications.

Fertility matters

Fertility preservation is one of the most important practical issues highlighted in the webinar. Many patients receiving gene therapy are adolescents and young adults. A treatment that potentially removes the need for lifelong transfusion or prevents recurrent vaso-occlusive disease can be transformative, but the treatment pathway may also threaten reproductive potential because of myeloablative busulfan.

This makes fertility counselling an essential part of treatment rather than an optional addition. Recent clinical data underline the seriousness of this issue. In a 2025 single-center study of 40 patients with SCD or transfusion-dependent beta thalassemia undergoing gene therapy, all female participants successfully underwent oocyte retrieval before treatment. However, among 17 women with more than one year of follow-up, all had evidence of ovarian failure with undetectable anti-Müllerian hormone levels.

The finding reinforces the need to discuss fertility preservation before conditioning begins. For males, sperm cryopreservation is generally more straightforward. For females, ovarian stimulation and oocyte or embryo cryopreservation may be possible, while ovarian tissue cryopreservation remains an important option in selected younger patients.

Real-world activity

During the 2024/2025 reporting period, the National Haemoglobinopathy Programme multidisciplinary team received 25 gene therapy referrals. The referral data shown in the presentation include both transfusion-dependent thalassemia and sickle cell disease, demonstrating that the service is already dealing with a mixed population rather than a single disease pathway. The presentation also reports 18 adult gene therapy referrals and seven pediatric referrals across its cellular therapy referral dataset.

More importantly, the approval data suggest that most referred patients were considered suitable for treatment. Among the 25 cases presented, 94% of adult gene therapy referrals and 100% of pediatric referrals were approved, while 6% of adult referrals were recorded as not currently recommended. This is a striking finding because it demonstrates that referral itself does not necessarily represent treatment rejection. Instead, the multidisciplinary assessment appears to function as a mechanism for identifying patients who can proceed safely and those who require further optimization.

The referral numbers also illustrate the growing overlap between gene therapy and conventional cellular therapy. In the webinar’s referral dataset, adult HSCT and pediatric HSCT each accounted for 20 referrals, while adult gene therapy accounted for 18 and pediatric gene therapy for seven.
This is important because gene therapy should not be viewed as replacing transplantation overnight. Instead, specialist programs are now making decisions across several potentially curative cellular treatment pathways.

Access is more than Eligibility

The emergence of gene therapy does not automatically mean universal access.
A patient can meet the biological criteria but still face barriers involving geography, referral pathways, funding, family support, fertility services or specialist capacity.
Haemoglobinopathy services are not always co-located with transplant or cellular therapy facilities. This creates additional complexity when patients need coordinated assessment, stem cell collection, conditioning and long-term follow-up.

For SCD, additional issues may arise from red cell alloimmunization, chronic pain and complex transfusion histories. Patients may also have accumulated organ damage that complicates intensive conditioning.
The UK has responded by developing highly specialized centers capable of delivering gene therapy within a controlled cellular therapy infrastructure. NICE has recommended exa-cel under managed access for selected patients with severe SCD and for transfusion-dependent beta thalassemia.

For SCD, the current NHS criteria include patients aged 12 years or older with recurrent vaso-occlusive crises and specified genotypes when HSCT is appropriate but a matched related donor is unavailable.
The economic dimension is substantial. The listed price of exa-cel in England is £1.651 million per treatment before the confidential commercial discount.

This means that healthcare systems must consider not only the immediate cost but also the long-term consequences of reducing transfusions, hospital admissions, complications and chronic treatment. The real-world value of gene therapy will therefore depend on whether health systems can deliver it safely, equitably and sustainably.

Beyond the first Treatment

The phrase one-time therapy can create an impression that clinical follow-up ends after infusion. It does not. Gene therapy patients require prolonged monitoring because the durability of treatment and the possibility of late adverse events cannot be fully established from early clinical trials.

Exa-cel programs include long-term follow-up extending to 15 years.This long-term surveillance is particularly important for gene-editing approaches because patients have received genetically modified autologous stem cells. Although current clinical data have not identified a new malignancy signal with exa-cel, the duration of observation remains limited relative to a patient’s lifetime.

The same principle applies to disease outcomes. In thalassemia, transfusion independence is an extraordinary endpoint, but clinicians must continue to monitor iron burden, endocrine health, bone health and organ function. In SCD, elimination of vaso-occlusive crises is a major achievement, but existing organ damage may not immediately reverse.

Patients may continue to require surveillance for renal, pulmonary, neurological and other complications. Longer-term data are becoming increasingly encouraging. By 2025, follow-up from exa-cel programs extended beyond five years for SCD and beyond six years for transfusion-dependent thalassemia. In the combined long-term analyses, durable hematologic improvement and stable genetic editing have been reported, with no malignancies observed through the available follow-up.

For thalassemia, particularly important data show that 55 of 56 participants had achieved at least 12 months of transfusion independence in the 2025 analysis, while 38 had discontinued iron removal therapy. These findings suggest that the effect of treatment may extend beyond transfusion avoidance toward correction of the abnormal iron physiology associated with ineffective erythropoiesis.

A Changing definition of Success

The most important lesson from the UK experience is that the success of gene therapy cannot be measured by clinical trial endpoints alone.
For a patient with transfusion-dependent beta thalassemia, success may mean no longer requiring regular transfusions, reducing or stopping iron chelation, restoring normal hemoglobin production and gaining greater freedom in education, employment, relationships and family planning.

For someone with severe sickle cell disease, success may mean freedom from painful vaso-occlusive crises, fewer hospital admissions and the opportunity to live without the constant anticipation of the next crisis.
But for the healthcare system, success also means that these outcomes can be delivered safely and reproducibly.
The webinar’s real-world data demonstrate why implementation requires a comprehensive approach. Liver health must be assessed.

Iron burden must be controlled. Stem cells must be collected efficiently. Apheresis services must be available. Fertility preservation must be incorporated early. Conditioning toxicity must be managed. Manufacturing must be reliable. Multidisciplinary teams must make careful eligibility decisions. Long-term surveillance must continue after treatment.

Future Direction

The next stage of development will focus on making gene therapy safer, simpler and accessible to a broader population. One priority is conditioning. Current approaches depend on myeloablative chemotherapy, with busulfan remaining central to successful treatment.

Developing targeted conditioning that selectively clears the marrow niche without damaging reproductive organs or other tissues could dramatically change the treatment pathway. Another priority is expanding eligibility. Patients with advanced liver disease, severe iron overload or significant organ dysfunction may currently be unsuitable for intensive conditioning.

Safer conditioning could allow these patients to benefit. The treatment process itself may also become less burdensome. Improvements in mobilization, apheresis, manufacturing efficiency and cryopreservation could reduce the number of hospital visits and treatment delays.  In the longer term, in vivo gene editing could potentially eliminate the need for ex vivo cell collection and manufacturing altogether, although this remains an investigational concept.

The field is also moving toward younger patients. Exa-cel studies are already evaluating children below the current adult and adolescent treatment population, reflecting the possibility that correcting the underlying disease earlier could prevent irreversible organ damage rather than attempting to reverse it later. Digital infrastructure will also matter. Long-term gene therapy programs will need integrated systems capable of tracking blood counts, transfusion requirements, iron burden, organ function, fertility outcomes and late adverse events over many years.

Conclusion

Gene therapy has crossed an important threshold in haemoglobinopathy care, but its real impact will be determined outside the clinical trial environment.
The UK experience presented in the webinar shows that successful treatment depends on far more than genetic editing. Patient selection, liver health, iron burden, stem cell mobilization, apheresis, conditioning, fertility preservation, specialist infrastructure and long-term surveillance all determine whether a theoretically eligible patient can safely receive treatment.

Clinical evidence demonstrates the transformative potential of exa-cel, with high rates of transfusion independence in beta thalassemia and sustained freedom from severe vaso-occlusive crises in sickle cell disease. The emerging real-world experience now adds an equally important message. The future of gene therapy is not simply about developing a treatment that works. It is about building a clinical pathway capable of delivering that treatment safely, equitably and sustainably.

References