title: Helper-dependent adenoviral liver gene therapy protects against induced attacks and corrects protein folding stress in acute intermittent porphyria mice.
abstract: Acute intermittent porphyria (AIP) is a hepatic metabolic disease that results from haplo-insufficient activity of porphobilinogen deaminase (PBGD). The dominant clinical feature is acute intermittent attacks when hepatic heme synthesis is activated by endocrine or exogenous factors. Gene therapy vectors over-expressing PBGD protein in the liver offers potential as a cure for AIP. Here, we developed a helper-dependent adenovirus (HDA) encoding human PBGD (hPBGD) and assessed its therapeutic efficacy in a murine model of AIP. Intravenous or intrahepatic administration of HDA-hPBGD to AIP mice resulted in a sustained hepatic hPBGD expression in a dose-dependent manner. Intrahepatic administration conveyed full protection against induced porphyria attacks at a significantly lower viral dose than intravenous injection. Transgenic hPBGD accumulated only in the cytosol of hepatocytes as the endogenous protein. Characterization of PBGD-deficient mouse strains revealed that a strong PBGD deficiency causes the chronic disturbance of cytosolic and endoplasmic reticulum folding machineries. This disturbance was completely restored over time by the over-expression of hPBGD. HDA-hPBGD is a promising vector that protects against porphyria attacks and resolves the chronic folding stress associated with low levels of PBGD activity.
authors.affiliation: Gene Therapy and Hepatology Area, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Unzu
authors.forename: Ana
authors.initials: A
authors.lastname: Sampedro
authors.forename: Itsaso
authors.initials: I
authors.lastname: Mauleón
authors.forename: Manuela
authors.initials: M
authors.lastname: González-Aparicio
authors.forename: Rafael
authors.initials: R
authors.lastname: Enríquez de Salamanca
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Tomás
authors.initials: T
authors.lastname: Aragón
authors.forename: Antonio
authors.initials: A
authors.lastname: Fontanellas
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology; D022781:Hepatocytes / Q000201:enzymology / Q000821:virology; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017118:Porphyria, Acute Intermittent / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control / Q000628:therapy*; D017510:Protein Folding
chemical_list: D011163:Hydroxymethylbilane Synthase