Adeno-associated virus (AAV) vectors are a leading platform for gene-based therapies for both monogenic and complex acquired disorders. The success of AAV gene transfer highlights the need to answer ...outstanding clinical questions of safety, durability, and the nature of the human immune response to AAV vectors. Here, we present longitudinal follow-up data of subjects who participated in the first trial of a systemically delivered AAV vector. Adult males (n = 7) with severe hemophilia B received an AAV2 vector at doses ranging from 8 × 1010 to 2 × 1012 vg/kg to target hepatocyte-specific expression of coagulation factor IX; a subset (n = 4) was followed for 12–15 years post-vector administration. No major safety concerns were observed. There was no evidence of sustained hepatic toxicity or development of hepatocellular carcinoma as assessed by liver transaminase values, serum α-fetoprotein, and liver ultrasound. Subjects demonstrated persistent, increased AAV neutralizing antibodies (NAbs) to the infused AAV serotype 2 (AAV2) as well as all other AAV serotypes tested (AAV5 and AAV8) for the duration of follow-up. These data represent the longest available longitudinal follow-up data of subjects who received intravascular AAV and support the preliminary safety of intravascular AAV administration at the doses tested in adults. Data demonstrate, for the first time, the persistence of high-titer, multi-serotype cross-reactive AAV NAbs for up to 15 years post- AAV vector administration. Our observations are broadly applicable to the development of AAV-mediated gene therapy.
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Presented here are the longest available longitudinal follow-ups of human subjects following intravascular adeno-associated virus (AAV) vector administration. These data support the preliminary long-term safety of systemic AAV delivery and demonstrate the persistence of high-titer, multi-serotype, cross-reactive AAV NAbs for up to 15 years after vector infusion.
An adeno-associated viral vector was used to introduce a
FIX
gene with enhanced biologic activity in 10 participants with hemophilia B. The annualized bleeding rate was 11.1 events per year before ...therapy versus 0.4 afterward. Steady-state factor IX levels were 33.7% of normal.
Endogenous and exogenous hormones have significant effects on coagulation and may tip the hemostatic balance toward thrombosis. The endogenous hormonal changes in pregnancy and polycystic ovary ...syndrome, and exogenous hormonal contraception, menopause replacement, and transgender cross-hormone replacement may increase thromboembolism risk. Using the lowest effective dose is critical for prevention, but once thrombosis occurs, anticoagulation may be required, in some, long term. We review the relative risk of thrombosis in these conditions, risk factors, and anticoagulation treatment and prevention. Implementation of lowest effective hormonal therapies, thrombosis reduction strategies, and current anticoagulation management are critical for optimal patient outcomes.
In a study involving patients with severe hemophilia A, an injection of the novel fusion protein BIVV001 resulted in a duration of factor VIII activity that was up to four times as long as that for ...recombinant factor VIII, an increase that may signal the possibility of weekly therapy.
Fitusiran is an RNA interference therapeutic that targets antithrombin (AT) in the liver and interferes with AT translation by binding and degrading messenger RNA-AT, thereby silencing AT gene ...expression and preventing AT synthesis. In both preclinical and clinical studies, AT knockdown results in dose-dependent AT lowering when fitusiran is given weekly or monthly subcutaneously. In clinical trials, fitusiran dose escalation has resulted in improved thrombin generation and clinical hemostasis as measured by reduction in annualized bleed rate. Unlike currently licensed drugs, this improvement was not only in patients with hemophilia A but in also those with hemophilia B, with or without inhibitors. In dental and surgical procedures, fitusiran also provided perioperative hemostasis in association with AT lowering. Fitusiran is well tolerated, with minor local injection site reactions, but in one subject with severe hemophilia A, the concomitant use of daily high-dose factor VIII, inconsistent with trial guidance to avoid high, repeat doses of clotting factor, was associated with fatal thrombosis, suggesting the need for caution when using hemostatic agents in conjunction with fitusiran. Preclinical in vitro and in silico studies indicate improvement in thrombin generation in rare bleeding disorder plasmas, including in plasmas from patients with severe factors V, VII, and X deficiency, suggesting potential therapeutic benefit.
At a median follow-up of 3.5 years after gene therapy with a factor VIII–containing adeno-associated virus, 16 of 18 men with hemophilia A had enough factor VIII expression that bleeding events were ...reduced to nearly zero and prophylaxis was discontinued. Vector-related hepatitis led to elimination of the vector in 2 men, but immunosuppressive therapy helped to maintain expression in the others.
Abstract
von Willebrand disease (VWD) is a quantitative or qualitative defect in von Willebrand factor (VWF) resulting in mucocutaneous bleeding symptoms and hemorrhage following hemostatic ...challenges, such as trauma or surgery. VWD-specific therapy, DDAVP (1-desamino-8-D-arginine vasopressin) and VWF concentrates, is necessary periprocedurally to ensure adequate hemostasis. The aging VWD patient may complicate this matter. The plasma concentration of many coagulation proteins, including VWF, increases with age. While it has been established that VWF levels increase with age in a healthy population, emerging research demonstrates this occurs in certain subtypes of VWD, too. Thus, the management of periprocedural VWD-specific therapy in the aging VWD patient is problematic when VWF levels increase over time to normal, and hematologists are left with uncertainty regarding whether or not periprocedural VWD-specific therapy is still necessary. In this article, we will review the current state of the literature regarding the effect of age on VWF levels in the healthy population and VWD while exploring possible etiologies for this phenomenon. Further, we will detail how this affects bleeding symptoms and highlight what research remains to be done to optimize care in this patient population.
The prophylactic treatment of hemophilia involves the replacement of factor VIII or IX in affected persons. A new approach involves the depletion of the clot inhibitor antithrombin.
Hemophilia is an ...X-linked bleeding disorder resulting from a deficiency of coagulation factor VIII or IX (causing hemophilia A or B, respectively) and is characterized by spontaneous and traumatic bleeding into the muscles, joints, and body cavities. Treatment is expensive, with an annual cost of several hundred thousand dollars for an average adult, and the complications of bleeding often result in greater severity of disease, poor quality of life, a requirement for orthopedic surgery, and a shortened life span. To prevent bleeding and its complications, the missing coagulation factor is replaced several times weekly by means of an intravenous infusion, . . .
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