151 Long term correction of bilirubin UDP glucuronyltransferase deficiency in rats by in utero lentiviral gene transfer

Regenerative Therapies for Liver Diseases

“…Long-Evans cinnamon rats are a model of Wilson disease and transfer of the ATP7B gene to hepatocytes ameliorates both biochemical and histological pathologies [165]. Transgene products released into blood circulation after successful gene transfer into the hepatocytes corrected pathological manifestation both inside and/or outside of the liver in glycogen storage diseases (type Ia, [166] Ib [167] and II [167], mucopolysaccharidosis type I [168], IIIB [169] and VII [170], hereditary tyrosinemia type I [171], UDP glucuronyltransferase deficiency (Crigler-Najjar type I) [172], and hemophilia [173][174][175].…”

“…Unfortunately, however, the development of inhibitory antibodies against the exogenous factor IX and/or components of viral vectors diminished a persistent phenotypic correction [181,182]. One possible solution to avoid antibody development against exogenous gene products is gene delivery into the fetal liver to induce tolerance to the exogenous gene products [172,175,183] or alternative injection routes [184]. It is important to point out that significant difference exists between animal studies and human clinical trials with respect to immunological reactions [185,186].…”

Progress toward liver‐based gene therapy

“…Unfortunately, however, the development of inhibitory antibodies against the exogenous factor IX and/or components of viral vectors diminished a persistent phenotypic correction 164,172 . One possible solution to avoid antibody development against exogenous gene products is gene delivery into the fetus liver to induce tolerance to the exogenous gene products 126,131,173 . Selection of an alternative injection route would be another solution.…”

“…164,172 One possible solution to avoid antibody development against exogenous gene products is gene delivery into the fetus liver to induce tolerance to the exogenous gene products. 126,131,173 Selection of an alternative injection route would be another solution. For example, instead of systemic injection, the results of gene delivery by adenoviral vectors through the bile ducts showed possibility of repeated gene transfer of the viral vectors, even in the presence of neutralizing antibodies.…”

“…Long‐Evans cinnamon rats are a model of Wilson disease, and transfer of ATP7B gene to the hepatocytes ameliorates both biochemical and histological pathologies 119 . Transgene products released into blood circulation after successful gene transfer to the hepatocytes corrected pathological manifestation both inside and/or outside of the liver in glycogen storage diseases (type Ia, 120 Ib 121 and II 121 ), mucopolysaccharidosis (type I, 122 IIIB 123 and VII 124 ), hereditary tyrosinemia type I, 125 UDP glucuronyltransferase deficiency (Crigler‐Najjar type I), 126 and hemophilia 127–131 . It was also reported that the fibroblasts from a patient with Pompe disease (glycogen storage diseases type II) show acid alpha‐glucosidase (GAA) activity comparable to that in normal fibroblasts, when co‐cultured with fibroblasts transduced by adenovirus encoding human GAA 132 .…”