Update on clinical gene therapy for hemophilia

Abstract

In contrast to other diverse therapies for the X-linked bleeding disorder hemophilia that are currently in clinical development, gene therapy holds the promise of a lasting cure with a single drug administration. Near-to-complete correction of hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) have now been achieved in patients by hepatic in vivo gene transfer. Adeno-associated viral vectors with different viral capsids that have been engineered to express high-level, and in some cases hyperactive, coagulation factors were employed. Patient data support that sustained endogenous production of clotting factor as a result of gene therapy eliminates the need for infusion of coagulation factors (or alternative drugs that promote coagulation), and may therefore ultimately also reduce treatment costs. However, mild liver toxicities have been observed in some patients receiving high vector doses. In some but not all instances, the toxicities correlated with a T-cell response directed against the viral capsid, prompting use of immune suppression. In addition, not all patients can be treated because of preexisting immunity to viral capsids. Nonetheless, studies in animal models of hemophilia suggest that the approach can also be used for immune tolerance induction to prevent or eliminate inhibitory antibodies against coagulation factors. These can form in traditional protein replacement therapy and represent a major complication of treatment. The current review provides a summary and update on advances in clinical gene therapies for hemophilia and its continued development.

How I manage severe von Willebrand disease

“…Gene therapy has only been investigated in a preclinical setting for VWD (De Meyer et al , ; Wang et al , ; Portier et al , ). In patients with haemophilia, gene therapy has shown very good results in clinical trials (Perrin et al , ). Compared to haemophilia, gene therapy for VWD seems more challenging, mainly because of the large size of the VWF gene, which makes it difficult to insert VWF cDNA in viral gene transfer vectors.…”

Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia

“…All four were treated with steroids and no other serious adverse events occurred. The mean ABR decreased by 97% and mean annualized FVIII infusions decreased by 94% . Recently, BioMarin provided an update of clinical trial at the end of 3 years of dosing.…”

Modern approaches in hemophilia therapy

“…Первоначальный барьер неэффективной доставки генетического материала в клетки-и ткани-мишени преодолевается путем присоединения вирусных векторов, полученных из вирусов млекопитающих, которые содержат минимальные вирусные последовательности дикого типа, а их патогенные, репликативные и структурные вирусные гены заменены терапевтической генной кассетой. За прошедшие годы перенос генов печени in vivo с использованием аденоассоциированных вирусных векторов (ААВ) показал наибольшие успехи в доклинических и клинических исследованиях [36]. ААВ получены из ААВ дикого типа 8, члена семейства парвовирусов.…”