Novel treatments for hemophilia through rebalancing of the coagulation cascade

Abstract

Hemophilia A and B are inherited hemorrhagic disorders that result from alterations in the coagulation cascade. Aside from spontaneous bleeding, the main complication of hemophilia is hemarthrosis. Progress over the last three decades, specifically prophylaxis using recombinant factor, has prevented hemarthrosis and lengthened patient life expectancies. However, many treatments require frequent dosing up to three times a week, and alloantibodies (inhibitors) against replacement factor continues to be an issue. These problems call for novel treatments for patients with hemophilia. Although there has been progress in extended half‐life factors and mimetics of factor VIII, an alternative treatment methodology is to rebalance the activities of pro‐ and anticoagulant factors through inhibition of the natural anticoagulants: antithrombin, tissue factor pathway inhibitor, protein C, and protein S. This review will explore the efficacy of targeting these inhibitory pathways from preclinical development through clinical trials, and delve into concerns of thrombotic risk.

In vitro recovery of FIX clotting activity as a marker of highly functional hepatocytes in a hemophilia B iPSC model

“…However, this treatment presents certain limitations such as the considerable constraints represented by these repeated injections, affecting the daily life of patients, and its potential side effects such as the development of neutralizing antibodies. [1] Two major treatment advances have recently emerged: (1) the use of recombinant FIX concentrates with a prolonged half-life [1] and (2) the gene therapy, which may enable a definitive cure for hemophilia. Indeed, HB is an ideal candidate for this strategy because it is a monogenic disease, [2] and the small size of FIX complementary DNA (cDNA; 1389bp) allows its insertion into most gene therapy vectors.…”

“…However, this treatment presents certain limitations such as the considerable constraints represented by these repeated injections, affecting the daily life of patients, and its potential side effects such as the development of neutralizing antibodies. [ 1 ]…”

“…Two major treatment advances have recently emerged: (1) the use of recombinant FIX concentrates with a prolonged half‐life [ 1 ] and (2) the gene therapy, which may enable a definitive cure for hemophilia. Indeed, HB is an ideal candidate for this strategy because it is a monogenic disease, [ 2 ] and the small size of FIX complementary DNA (cDNA; 1389bp) allows its insertion into most gene therapy vectors.…”

Hemofilia A: una enfermedad huérfana

“…Entre las aproximaciones terapéuticas recientes, también se encuentran anticuerpos específicos que simulan la función coagulante del FVIII [37], inhibición de proteínas anticoagulantes, como la antitrombina, con moléculas de interferencia del ARN, y la vía inhibidora del factor tisular con anticuerpos monoclonales [38][39][40].…”

Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe3O4 Nanoparticles

“…Several rebalancing agents have been developed and demonstrated their efficacy in hemophilia A animal experiment and hemophilia patients in clinical trial. It might be a potential candidate to treat hemophilia A in the future [ 14 ].…”