Sustained and therapeutic delivery of factor IX in nude haemophilia B miceby encapsulated C2C12 myoblasts: concurrent tumourigenesis

This study reports the generation of an immunodeficient murine model for ha emophilia B, obtained by breeding factor IX-deficient mice with an immunode ficient mouse strain, and use of this mouse model to evaluate the long-term efficacy and safety of a gene therapy strategy for treating haemophilia B. Nude haemophilic mice were implanted with biocompatible microcapsules encl osing recombinant myoblasts secreting human factor IX. The activated partia l thromboplastin time (APTT) of plasma of mice thus treated was invariably shortened 3 weeks after microcapsule implantation, and remained shortened f or at least 77 days. Shortening of the APTT of the haemophilia mice coincid ed with the appearance of human factor IX in mice plasmas (up to 600 ng mL( -1) on day 77), and normalization of the tail-bleeding time. Thus, the micr oencapsulated myoblasts reversed the clinical phenotype of haemophilia B. I n contrast, plasmas of immunocompetent haemophilic mice similarly implanted with microcapsules only showed a transient shortening of APTT, and coincid ent transient delivery of human factor IX antigen. Rapid disappearance of h uman factor IX from plasmas of immunocompetent mice also coincided with pro duction of antibodies to the human transgene. Significantly, 86% of the nud e haemophilia mice developed tumours of myoblast origin. Thus, while this s tudy revealed the feasibility of this gene therapy approach to treat severe haemophilia B, it also highlights the importance of using safer cell lines to prevent tumour development.