10  Gene therapy


Jan Astermark

Department of Translational Medicine, Lund University, Malmö, Sweden and Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Malmö, Sweden

Maria Magnusson

Coagulation Unit, Department of Hematology, Karolinska University Hospital, Stockholm, Sweden and Clinical Chemistry and Blood Coagulation Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

Fariba Baghaeri

Sahlgrenska University Hospital, Gothenburg, Sweden

Peter Kampmann

Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

1 Introduction

  • Gene therapy has proved to be effective in hemophilia management and may offer the potential to overcome some of the limitations of current therapeutic options [13].

  • The treatment is approved by EMA and used in some European countries for routine clinical practise.

  • Currently, it is not available outside clinical trials in the Nordic region, but a potential health technology assessment (HTA)-approval of gene therapy in the near future should be considered, since, whenever approved and reimbursed, it will present a challenge and require an extensive preparation and partly re-organization of the hemophilia infrastructure in each Nordic country.

  • To this end, a Nordic preparatory project was initiated in 2022 in order to facilitate and implement an effective infrastructure for the safe introduction of gene therapy and other potential genetically modified organism (GMO) agents with a function-based working model,addressing critical milestones including organization, patient selections and eligibility, product handling, administration, and follow-up [4].

2 Principles

  • The current concept of gene therapy for hemophilia includes the delivery of functional copies of the factor VIII or IX gene by viral vectors into the patient’s cells, enabling an endogenous production of the deficient factor [1,2].

  • Various vectors serve as delivery mechanisms to introduce the genetic material into the patient’s cells, mainly the hepatocytes. The most used and studied type of vector over the last decade has been the adeno-associated viruses (AAVs), but also other approaches such as lentiviruses have provided promising results and will be further evaluated.

  • AAVs have been favored for their safety profile with a low risk of integration in the host genome and ability to deliver genetic material to non-dividing cells, making them suitable for long-term expression.

  • Lentiviruses, on the other hand, can integrate the therapeutic gene into the patient’s genome, potentially providing a stable and enduring correction in also dividing cells making it more suitable for the growing child.

  • The current treatment options for both hemophilia A and B evaluated in phase 3 trials and approved by EMA all include various subtypes of AAV vector delivery [5,6], and research is on-going with the aim to refine the treatment and to ensure effective delivery, minimize the immune responses, and to enhance the overall success.

  • The specific factor levels achieved with gene therapy in hemophilia vary depending on the type of vector and individual patient characteristics, many of which are currently unknown, but basically a long-term expression for several years have been established in the majority of patients enabling them to reach sustained factor levels in the mild range i.e. sufficient levels to reduce or eliminate the need for regular factor replacement therapy.

3 Organization

  • The ‘hub-and-spoke’ model has been proposed as a framework of gene therapy [79].

  • Based on the structure of the health care in the Nordics, the original hub-and-spoke model will however not be fully applicable, but each country will potentially have one to three infusion sites with or without a collaboration with spoke center(s). In all countries, the local hospital and/or mobile teams will be involved for optimal sampling and follow-up.

  • To meet future requirements to establish GMO treatment in hemophilia, the multidisciplinary team will ideally include not only a hematologist, nurse, physiotherapist, orthopedic surgeon, but also a psychologist, social worker and hepatologist. This may require a collaboration between centers. In addition, how to access laboratory analyses within 24 hours of collection should be discussed and defined, including the availability of both the one-stage clotting assay and the chromogenic substrate assay.

  • The pharmacy unit will play a key role in the preparation and administration of the vector (gene therapy product) at each center, but the set-up will differ between countries and centers.

  • For future management of GMO products, Advanced Therapy Medicinal Product (ATMP) centers are currently being organized in several of the University hospitals. These centers will presumably in most locations be involved in vector preparation and delivery, but supervised by and in close collaboration with the local multidisciplinary hemophilia care team.

4 Patient selection

  • Early information and counselling about treatment options and expectations of gene therapy should be provided on several occasions to all potentially eligible patients during the pre-dosing process.

  • Patients should understand that although gene therapy may convert them from a severe to a mild phenotype, they should not be considered as cured and they will continue to need clinical monitoring independent of the expression level.

  • In addition to what is stated in the Summary of Product Characteristics (SmPC) about contraindication/cautiousness for vector delivery, the review of therapeutics and co-morbidities, all candidates must be given sufficient information in order to understand and consent to the commitments and potential risks involved.

  • The requirement post-infusion for abstinence from alcohol for up to a year after the vector is administered need an extra focus and discussion, as does the need for the use of barrier and effective contraception throughout the period of vector shedding (see below).

  • The likelihood of a cytotoxic immune response occurring, and the subsequent need for treatment with immunosuppressive agents (mainly corticosteroids) for several weeks post-infusion should also be addressed.

  • Patient education should take individual health, literacy, diverse social and educational background, language barriers and learning mechanisms into account. A broad pallet of educational tools should be provided, including face-to-face sessions, and the provision of written and visual aid materials are of paramount importance in providing equal access to gene therapy.

  • A shared decision-making process based on a designed pre-infusion checklist has been defined to ensure that all preparatory work has been performed and that adequate information has been provided to the patient/family (Figure 1).

5 Eligibility testing

  • The eligibility criteria for gene therapy may differ, and should follow the guidelines in the relevant SmPC.

  • Accurate measurement of anti-AAV antibodies will be crucial, and each manufacturer will presumably offer mandatory companion diagnostics to be used.

  • In addition, a centralized method for AAV-serotype testing at one or more of the Nordic centers have been discussed to enable the possibility of testing for different serotypes of AAV independent of the product manufacturer.

  • An initial first screening in the early phase of communication, during the pre-infusion period, should be performed followed by a follow-up testing closer to the time of dosing – preferably 3-4 weeks pre-infusion.

  • An accurate and appropriate liver assessment for evaluating patient eligibility will be important [10].

  • The decision limit of liver enzyme levels for eligibility for gene therapy should also follow the guidance that is stated in the relevant SmPC, but all pathological findings need to be scrutinized.

  • Active infections need to be ruled out, and subjects who have been treated and cured of hepatitis C virus infection must have two negative viral assays performed by polymerase chain reaction at least 6 months apart.

  • Fibroscan, liver ultrasound and fibrosis-4 score for liver fibrosis should be performed on all eligible patients to screen for advanced liver fibrosis or liver cirrhosis.

6 Vector infusion

  • A general working sheet or checklist for the preparation and delivery of the vector should be developed at each center and include a planning of all logistics with the patient, ward, emergency equipment, intensive care unit and the pharmacy two weeks pre-infusion.

  • The dose (vg/kg) to be administered and infusion rate will follow the SmPC for each agent.

  • The patient should be carefully observed during the entire infusion period including frequent blood pressure, heart rate and temperature according to a pre-defined protocol.

  • On day 1 post-infusion before discharge, the procedure should be reviewed with the patient, follow-up discussed and the commitments confirmed, as well as any post-infusion thoughts/concerns identified.

7 Follow-up

  • Follow-up visits will generally be performed at the hemophilia comprehensive care (infusion) center and include a general laboratory work-up including liver assessment, inflammatory markers, factor activity levels including inhibitor testing whenever indicated.

  • The content and minimal timing of these visits/sampling time points will mainly follow the recommendations of the World Federation of Hemophilia (WFH), as outlined in Figure 2, but during the first 3-6 months, sampling and monitoring will be performed more frequently, basically every week.

  • For patients living far away from the center, blood sampling may be performed at the patient’s local hospital and/or by mobile teams. Anagreement, between the mobile unit/nurses and the responsible center, should be signed and responsibilities defined.

  • A turn-around-time (TAT) of 24 hours for both factor activity analyzes and liver enzymes will be required, and availability of these analyzes at weekends may require extra consideration.

  • In addition to the plasma laboratory work-up, and irrespective of any fibroscanning, ultrasound of the liver is recommended – as for all other patients with a history of hepatitis B and/or C infection – every 6-12 months, for early identification of hepatocellular carcinoma.

  • Vector shedding should be assessed according the SmPC of each approved GMO product. During the period of vector shedding, all patients (also including vasectomized patients) should use contraception including condoms, and not donate any cells and/or tissues including semen – usually up to 6 months post-infusion – and longer if required.

8 Registry

  • Proper data collection and registration in the national registries will be crucial and each national registry in the Nordics will harmonize the parameters to be documented together.

  • In addition, data will be provided to the WFH Gene Therapy Registry, manually or automatically, and the Nordic centers will take part in the planned accreditation process by EAHAD.


  • Gene therapy should be considered as a new treatment option for adult patients with severe hemophilia.


  • An infrastructure for the safe introduction of gene therapy in the routine clinical setting should be established at each infusion center.


  • Education of patients and the expanded health care professional team will be the key to successful and optimal clinical management and a shared decision making process.


  • Close long-term follow-up and proper data collection with registration in the national registries as well as WFH gene therapy registry will be crucial for optimal clinical management.

9 Tables

Figure 1: Table 1
Figure 2: Table 2