Advanced therapies for the treatment of hemophilia: future perspectives

Abstract

Monogenic diseases are ideal candidates for treatment by the emerging advanced therapies, which are capable of correcting alterations in protein expression that result from genetic mutation. In hemophilia A and B such alterations affect the activity of coagulation factors VIII and IX, respectively, and are responsible for the development of the disease. Advanced therapies may involve the replacement of a deficient gene by a healthy gene so that it generates a certain functional, structural or transport protein (gene therapy); the incorporation of a full array of healthy genes and proteins through perfusion or transplantation of healthy cells (cell therapy); or tissue transplantation and formation of healthy organs (tissue engineering). For their part, induced pluripotent stem cells have recently been shown to also play a significant role in the fields of cell therapy and tissue engineering. Hemophilia is optimally suited for advanced therapies owing to the fact that, as a monogenic condition, it does not require very high expression levels of a coagulation factor to reach moderate disease status. As a result, significant progress has been possible with respect to these kinds of strategies, especially in the fields of gene therapy (by using viral and non-viral vectors) and cell therapy (by means of several types of target cells). Thus, although still considered a rare disorder, hemophilia is now recognized as a condition amenable to gene therapy, which can be administered in the form of lentiviral and adeno-associated vectors applied to adult stem cells, autologous fibroblasts, platelets and hematopoietic stem cells; by means of non-viral vectors; or through the repair of mutations by chimeric oligonucleotides. In hemophilia, cell therapy approaches have been based mainly on transplantation of healthy cells (adult stem cells or induced pluripotent cell-derived progenitor cells) in order to restore alterations in coagulation factor expression.

Five-Year Data of Clinical Characteristics and Laboratory Findings of Hospitalized Hemophilic Patients in Dr. Hasan Sadikin General Hospital

“…About 60-70% from the total hemophilic population worldwide is in the severe factor level deficiency. Regarding the type of hemophilia, a previous study by Liras et al 2 showed that 40% of cases of hemophilia A and hemophilia B, respectively, contributes to severe level of factor deficiency. In this study, about 75-80% of patients for each type was distributed in the severe level.…”

“…Hemophilia is an X-linked disease caused by mutation in sex chromosome resulting in protein deficiency named coagulation factors. 1,2 Among several type of coagulation factors, deficiency factor VIII, IX, and XI occur in hemophilic patients. Deficiency of those factors contributed to a certain type of hemophilia, namely hemophilia A for factor VIII deficiency, hemophilia B for factor IX deficiency, and hemophilia C for factor XI deficiency.…”

“…Deficiency of those factors contributed to a certain type of hemophilia, namely hemophilia A for factor VIII deficiency, hemophilia B for factor IX deficiency, and hemophilia C for factor XI deficiency. 2 From 172.373 hemophilic cases worldwide in 2012, about 80% cases were hemophilia A, 16% cases were hemophilia B, and the rest was hemophilia C and other bleeding disorders. Because it is an x-linked disease, hemophilia is more common found in male than female.…”

A WOMAN WITH SPORADIC HEMOPHILIA-B DIE BECAUSE OF CEREBRAL BLEEDING: A Rare Case in Bali-Indonesia

“…1,8 Gene transfer is a future therapy for hemophilic, which is still a developing biological molecular therapy, but until now it can not changes hemophilic phenotype. 30 For our patient, the counseling, education, supportive therapy for acute bleeding management and fresh frozen plasma has been administered.…”

Production of Lentiviral Vectors Encoding Recombinant Factor VIII Expression in Serum-Free Suspension Cultures

“…Nevertheless, recent studies have shown that they have much lower oncogenic potential than other retroviruses because LV do not integrate with high frequency near promoters of proto-oncogenes and genes that control cell proliferation. Lentiviral gene therapy for hemophilia A has been successfully used in several pre-clinical studies (Liras et al 2012;Chuah et al 2013;High et al 2014) and is close to clinical approval. Furthermore, it has been favorably reviewed by the US Recombinant DNA Advisory Committee, as well as by the US Food and Drug Administration (FDA) (High et al 2014).…”