Gene Therapy for Inherited Bleeding Disorders

Abstract

Decades of preclinical and clinical studies developing gene therapy for hemophilia are poised to bear fruit with current promising pivotal studies likely to lead to regulatory approval. However, this recent success should not obscure the multiple challenges that were overcome to reach this destination. Gene therapy for hemophilia A and B benefited from advancements in the general gene therapy field, such as the development of adeno-associated viral vectors, as well as disease-specific breakthroughs, like the identification of B-domain deleted factor VIII and hyperactive factor IX Padua. The gene therapy field has also benefited from hemophilia B clinical studies, which revealed for the first time critical safety concerns related to immune responses to the vector capsid not anticipated in preclinical models. Preclinical studies have also investigated gene transfer approaches for other rare inherited bleeding disorders, including factor VII deficiency, von Willebrand disease, and Glanzmann thrombasthenia. Here we review the successful gene therapy journey for hemophilia and pose some unanswered questions. We then discuss the current state of gene therapy for these other rare inherited bleeding disorders and how the lessons of hemophilia gene therapy may guide clinical development.

Illustrated State‐of‐the‐Art Capsules of the ISTH 2022 Congress

“…Adeno‐associated viral vectors have emerged as one of the most promising gene delivery platforms for in vivo liver‐directed gene therapy for the treatment of blood coagulation disorders, particularly hemophilia A (HA) and B (HB). The ongoing clinical trials are based on adeno‐associated virus (AAV)‐mediated hepatocyte‐targeted expression of coagulation factor VIII or IX for HA and HB, respectively 13 . Nevertheless, there is increasing interest in the possibility of improving the targeting of different cell types.…”

Gene Therapy in Hemophilia: Recent Advances

“…Recent work in gene therapy aimed at developing a treatment for congenital coagulopathies has instilled renewed hope in patients with HA and HB [ 4 ]. Use of different AAV vector genotypes has already yielded concrete, nd highly encouraging, results in clinical trials in terms of the expression levels (moderate phenotype) and expression times (several months) achieved [ 30 ]. However, the problems related to the vectors’ immunogenicity and hepatotoxicity remain to be solved.…”

The Clinical Genetics of Hemophilia B (Factor IX Deficiency)

“…20 Some methods of gene therapy for HB are currently in clinical trials, as discussed below. 21 It has long been suggested that HB is clinically less severe than HA. 22,23 This perception may be partially due to the fact that the distribution of severity is different in the two disorders (Table 1).…”

“… 78 Subsequent trials using the variant FIX-Padua, which has increased FIX production, and altered vectors have produced average FIX levels of 25–47%. 21 Thus, levels in the upper range of mild HB or the normal range can be achieved, altering the clinical phenotype. Clinical trials, including two in Phase 3, 79 are ongoing, as are those in animal models to answer questions surrounding the durability of the response, the need for immunosuppression, dose required, inhibitor risk, long-term liver effects, germline integration, and applicability to affected females.…”

“…Clinical trials, including two in Phase 3, 79 are ongoing, as are those in animal models to answer questions surrounding the durability of the response, the need for immunosuppression, dose required, inhibitor risk, long-term liver effects, germline integration, and applicability to affected females. 21 In addition, cost–benefit analyses of this expensive therapy are being carried out, and educational efforts directed to physicians and patients have been developed. 79 …”