Current animal models of hemophilia: the state of the art

Abstract

Hemophilia is the most well-known hereditary bleeding disorder, with an incidence of one in every 5000 to 30,000 males worldwide. The disease is treated by infusion of protein products on demand and as prophylaxis. Although these therapies have been very successful, some challenging and unresolved tasks remain, such as reducing bleeding rates, presence of target joints and/or established joint damage, eliminating the development of inhibitors, and increasing the success rate of immune-tolerance induction (ITI). Many preclinical trials are carried out on animal models for hemophilia generated by the hemophilia research community, which in turn enable prospective clinical trials aiming to tackle these challenges. Suitable animal models are needed for greater advances in treating hemophilia, such as the development of better models for evaluation of the efficacy and safety of long-acting products, more powerful gene therapy vectors than are currently available, and successful ITI strategies. Mice, dogs, and pigs are the most commonly used animal models for hemophilia. With the advent of the nuclease method for genome editing, namely the CRISPR/Cas9 system, it is now possible to create animal models for hemophilia other than mice in a short period of time. This review presents currently available animal models for hemophilia, and discusses the importance of animal models for the development of better treatment options for hemophilia.

A Foundational Study for Normal F8-Containing Mouse Models for the miRNA Regulation of Hemophilia A: Identification and Analysis of Mouse miRNAs that Downregulate the Murine F8 Gene

“…Available preclinical animal models for HA (rats, dogs, sheep, and genetically engineered mice and pigs) are all centered around developing appropriate therapies for HA [8]. Only recently, we have shown that miRNAs can influence the HA disease outcomes, including in patients with the normal F8 gene [4][5][6].…”

Escape or Fight: Inhibitors in Hemophilia A

“…Several preclinical animal models of HA are presently available which can be used for the development of new gene therapy strategies to treat HA, to evaluate safety, as well as for dosage and long-term follow-up studies. These models include HA animals with spontaneous mutations, such as dogs, sheep and rats, and genetically engineered animals, like mice and pigs (59). Moreover, the generation of a HA mouse model carrying the human HLA class II antigen, associated in humans with higher inhibitor development risk, has given us the possibility to better understand/characterize mechanisms involved in immune reaction against FVIII (20,60).…”

Does haemophilia slow down the development of liver fibrosis?

“…In this study, 48 patients with a medical history of clotting factor treatment for large joint bleeds were compared to a matched control group of 48 patients who did not receive treatment for joint bleeds. 6 During the study visit, all these participants were questioned on the occurrence, frequency…”

“…These well-characterized models have been extensively employed to evaluate new treatments. 6 In this report, we have studied the progression of chemically induced liver fibrosis by means of an haemophilia A mouse model.…”