Hemophilia and hereditary angioedema: nonreplacement and gene therapies expand prevention and long-term control
Blood clotting and vascular swelling: distinct regulatory disorders
Treatment for hemophilia and hereditary angioedema (HAE) has progressed from responding to bleeding or swelling after it occurs toward prevention and long-term control. A review published in the international journal Research and Practice in Thrombosis and Haemostasis compares advances in treatment for the two conditions. It is a review of the literature, distinct from a study reporting results from a new clinical trial.
The conditions cause different symptoms—bleeding and acute swelling, respectively—but both are associated with dysregulation in biological pathways involving serine proteases. In hemophilia A and B, a deficiency or dysfunction of clotting factor VIII or IX, respectively, leads to insufficient thrombin generation. In C1 inhibitor-deficient HAE, increased kallikrein activity and bradykinin production raise vascular permeability and cause swelling. Not all HAE is caused by C1 inhibitor deficiency.
Early treatment relied heavily on plasma-derived products given during bleeding or swelling attacks, though these were not the only treatments. Desmopressin, developed in the late 1970s, could be used for mild hemophilia A, but not hemophilia B.
From plasma-derived products to recombinant and nonreplacement therapies
The introduction of recombinant technology improved the safety and supply of replacement therapies for both conditions. The review notes that these advances occurred especially in high-income countries. For hemophilia, longer-acting recombinant clotting factors were also developed, allowing longer intervals between intravenous doses for prophylaxis.
More recently, nonreplacement therapies that do not directly replace the deficient protein have broadened preventive options. Emicizumab, a treatment for hemophilia A, is a bispecific antibody that links activated clotting factor IX and factor X to mimic the function of activated factor VIII. According to the review, it can be administered subcutaneously every 1–4 weeks. Rebalancing agents increase thrombin generation by reducing the activity of anticoagulant proteins in the body.
In HAE, the kallikrein–bradykinin pathway is targeted, but acute attack treatment must be distinguished from prevention. Icatibant, a bradykinin B2 receptor antagonist, is used during acute attacks, whereas the kallikrein-targeting antibody lanadelumab and the oral kallikrein inhibitor berotralstat are used to prevent attacks. Not every pathway-targeting drug is a preventive treatment.
Potential of gene and RNA therapies and their remaining limitations
Adeno-associated virus (AAV) vector-based gene therapy is advancing as a way to induce clotting factor production in people with hemophilia and reduce reliance on prophylaxis. Lentiviral hematopoietic stem cell gene therapy has also been attempted for hemophilia A. Challenges remain, particularly for hemophilia A, including individual variation in gene expression, the durability of factor VIII levels, immune responses, and associated liver toxicity.
Donidalorsen, an antisense oligonucleotide (ASO) therapy for HAE, targets prekallikrein messenger RNA to reduce attacks. It suppresses an overactive enzyme pathway; this does not mean that it corrects the genetic defect causing the disease.
Genome editing and strategies based on biomarkers and genotype are presented as directions for future development. The review describes a kallikrein gene-targeted editing therapy for HAE that reduced attacks in a phase 2 trial, but this cannot be interpreted as establishing a cure or lifelong freedom from attacks. Individualized treatment is moving toward consideration of clinical status and treatment response alongside genetic characteristics.
Source: Full review comparing treatment advances in hemophilia and hereditary angioedema.
Hemophilia and hereditary angioedema (HAE) are rare monogenic disorders characterized by the dysregulation of serine protease-based biological pathways, that is, blood coagulation and the kallikrein-kinin system. Although clinical manifestations differ profoundly (bleeding vs angioedema), both diseases have recently undergone parallel therapeutic revolutions, shaped by advances in molecular biology and biotechnology. Early management in the 1970s relied for both diseases on the episodic administration of plasma-derived products, subsequently replaced by recombinant products that improved safety and feasibility of prophylaxis regimens. In the last 20 years, the development of nonreplacement products, such as emicizumab and rebalancing agents in hemophilia and kallikrein/bradykinin pathway inhibitors in HAE, shifted clinical practice from the episodic management of clinical events to their prevention. More recently, gene and RNA-based therapies are further transforming both diseases toward curative attempts: in hemophilia, adeno-associated virus vector-mediated gene therapy and lentiviral stem-cell approaches; in HAE, antisense oligonucleotide-mediated kallikrein suppression. Emerging genome-editing approaches and biomarker- and genotype-driven strategies are poised to further improve and personalize treatment. The therapeutic trajectories of rare diseases such as hemophilia and HAE illustrate how mechanistic insights enable the transition from the episodic management of acute events to long-term disease control, offering prospects for curative interventions.
Treatment advances for these two conditions show that bleeding or swelling can be prevented by regulating disease pathways, in addition to replacing deficient proteins. When explaining treatment options, the purpose of each medicine must be distinguished. For example, emicizumab prophylaxis for hemophilia A, lanadelumab prophylaxis for HAE, and icatibant treatment for acute attacks address different situations. Gene and RNA therapies also cannot be grouped together as having the same meaning. Inducing clotting factor production in hemophilia and suppressing an overactive pathway in HAE have different goals, and their long-term effects and safety must be assessed separately. This review provides a framework for understanding treatment options, but it does not provide grounds for changing an individual patient's treatment or guarantee a cure.