Over the past decade, gene therapy has emerged as a groundbreaking new treatment option, particularly with the approval of products for haemophilia A and B. Thanks to the use of adeno-associated viruses (AAV) as vectors for the delivery of a functional gene to the body, these novel treatments promise a high degree of liberation from burdensome regular replacement therapy with coagulation factors.

This book presents the current knowledge on the potential of these new gene therapies in the treatment of haemophilia A and B. It covers the fundamentals of haemophilia as well as the various gene therapy approaches (AAV, lentivirus, gene editing), and includes specific aspects such as the selection of suitable patients for gene therapy, the effects on coagulation factor levels, liver-related issues, and the immune response to AAV-mediated gene therapy. The necessity of interdisciplinary collaboration and the innovative "hub and spoke" model are discussed.

This book is intended to serve as a bridge, closing the gap between current knowledge and future developments, and it aims to be a comprehensive source of information for professionals in both clinical practice and research.



1. Basic information about haemophilia 12

1.1. History 12

1.2. Clinical presentation 13

1.3. Therapy 13

2. Haemophilia gene therapy: recent advances and challenges 16

2.1. Phase III clinical trials of AAV gene therapies for the treatment of haemophilia A 18

2.2. Clinical phase III studies on AAV gene therapies for the treatment of haemophilia B 19

2.3. Gene editing 23

3. Which patients are eligible for gene therapy for haemophilia? 30

3.1. Inclusion and exclusion criteria in clinical trials of gene therapy for haemophilia 30

3.2. Patient-related factors as eligibility criteria for gene therapy 32

4. Influence of gene therapy on factor levels measured in the coagulation

laboratory 36

4.1. Assay discrepancies in the context of gene therapy for haemophilia A 37

4.2. Assay discrepancies in the context of gene therapy for haemophilia B 38

5. Liver-related problems in gene therapy – issues and solutions 44

5.1. Gene therapy-associated hepatitis 44

5.2. Mechanisms of hepatotoxicity 44

5.3. Liver cancer and AAV gene therapy 45

5.4. Management of liver disease in patient before, during and after gene therapy 46

6. Immune responses to AAV-mediated gene therapy in haemophilia 50

6.1. AAV vectors 50

6.2. AAV vector dose and immunotoxicity 51

6.3. Innate immune responses to AAV 51

6.4. Adaptive immune responses to AAV gene transfer 53

6.4.1. Pre-existing adaptive immunity to AAV 53

6.4.2. Antibody responses to AAV gene transfer 54

6.4.3. CD8+T cell responses to AAV gene transfer 57

6.5. Tregs 59

7. A practical approach to gene therapy for haemophilia –

the hub-and-spoke model 66

7.1. Special features of gene therapy for haemophilia 66

7.2. Challenges of gene therapy for haemophilia centres 67

7.3. Practical implications 67

7.3.1. Pre-treatment phase 68

7.3.2. Treatment phase 69

7.3.3. Post-treatment phase 69

8. Shared decision making for gene therapy in haemophilia care 74

8.1. Why is shared decision making important in haemophilia care? 74

8.2. Shared decision making and gene therapy for haemophilia 74

8.3. How do we ensure shared decision-making is a reality? 75

Index 79