The paradigm in the development of any novel therapeutic is that avoiding immune responses is more successful and desirable than attempting to eradicate an already established response. In an effort to avoid immune responses during gene transfer, recombinant vectors have been designed to contain few or no viral coding genes and avoid expression of pathogenic genes. Factors influencing the host immune response are the vector delivery (route of administration,

dose), choice of promoter/enhancer, alterations Linsitinib chemical structure to vector genome sequence and/or structure, the status and the nature of the target tissue (e.g. underlying disease or immune privileged sites) and patient-related factors (age, gender, immune status, drug

intake, co-morbid pathology); these factors are all critical to the development of a clinically relevant gene-based strategy to treat human diseases. [39]. Liver-specific promoters CH5424802 manufacturer are successful in inducing long-term, sustained expression of the therapeutic transgene in adult large animal models of haemophilia following delivery of adeno-associated viral (AAV) vectors [40–43], helper-dependent adenoviral vectors [44–46] or retroviral vectors to neonatal haemophilia dogs or mice [29]. Murine studies have shown that tolerance induction by liver-specific expression, is at least in part, an active suppressive mechanism involving the induction of a subset of Treg cells [29,47]. In non-human primate models, transient depletion of Treg cells at the time of AAV-FIX delivery to the liver prevents

tolerance to the transgene, which in turn, results in the formation of inhibitors to FIX [39]. The formation of inhibitors to FVIII is a major complication of treatment with FVIII concentrates, affecting ∼25% of severe HA patients. However, to date, it is still not possible to predict with certainty which patient will develop Phospholipase D1 an inhibitor to FVIII, thereby imposing challenges in implementing preventive strategies. The best-characterized risk factor is the type of underlying FVIII mutation. Given the inhibitor-associated morbidity resulting from limited and very expensive therapeutic options to control bleeds, inhibitor eradication is the ultimate goal of inhibitor management. Currently, immune tolerance induction (ITI) is the only strategy that has been proven to eradicate FVIII inhibitors successfully. ITI is based on daily injections of high doses of FVIII concentrates over long periods [48]. Therefore, it is possible that sustained expression of FVIII by gene therapy can mimic ITI leading to successful eradication of inhibitors. There are several HA animal models to test this hypothesis.