Progress and challenges in the development of a cell‐based therapy for hemophilia A

Abstract

Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review we discuss the possibilities, progress and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells (iPSCs) that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific iPSCs.

2017 Clinical trials update: Innovations in hemophilia therapy

“…The use of cell‐based gene therapy represents another therapeutic option for hemophilia . Several candidate cell types can support FVIII production: liver sinusoidal endothelial cells, stem cells derived from bone marrow, blood‐outgrowth endothelial cells, and endothelial progenitor cells derived from the differentiation of induced pluripotent stem cells .…”

Evaluation of high‐fat high‐fructose diet treatment in factor VIII (coagulation factor)‐deficient mouse model

“…; Fomin et al . ) can become unpredictable in such patients who exhibit NAFLD‐like condition due to various peripheral blood and liver immunological changes that occur. Although a definite study on human haemophilia A patients will provide a better insight, however, based on our study in F8 −/− mice, it is recommended that patients suffering from haemophilia A must avoid high fat and fructose diet which can lead to aggravated weight gain and hepatic steatosis.…”

“…If this is not monitored and taken into account then replacement therapy may not be completely effective as a remedy for the underlying disease condition. Also, the outcome of cell-based therapies where LSECs or unfractionated hepatocytes are transplanted (Kumaran et al 2005;Fomin et al 2014) can become unpredictable in such patients who exhibit NAFLD-like condition due to various peripheral blood and liver immunological changes that occur. Although a definite study on human haemophilia A patients will provide a better insight, however, based on our study in F8 À/À mice, it is recommended that patients suffering from haemophilia A must avoid high fat and fructose diet which can lead to aggravated weight gain and hepatic steatosis.…”

The search for the origin of factor VIII synthesis and its impact on therapeutic strategies for hemophilia A

“…MEIS1 and PBX3 are both members of the TALE (three amino acid loop extension) homeodomain-containcurrently challenging because of difficulties in accessing donor tissue, the estimated low yield of residual LSEC, and non-optimized culture systems. 18 However, the growing field of inducible pluripotent cells may provide useful alternatives. In addition, LSEC are also attractive for their ability to induce antigen-specific immune tolerance.…”