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	Carmen Unzu, Ana Sampedro, Itsaso Mauleón, Manuela González-Aparicio, Rafael Enríquez de Salamanca, Jesús Prieto, Tomás Aragón, Antonio Fontanellas
Journal	Human molecular genetics (Hum Mol Genet) Vol. 22 Issue 14 Pg. 2929-40 (Jul 15 2013) ISSN: 1460-2083 [Electronic] England
PMID	23562909 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Hydroxymethylbilane Synthase
Topics	Adenoviridae (genetics, physiology) Animals Disease Models, Animal Female Genetic Therapy Genetic Vectors (genetics, physiology) Hepatocytes (enzymology, virology) Humans Hydroxymethylbilane Synthase (genetics, metabolism) Liver (enzymology, virology) Male Mice Mice, Inbred C57BL Porphyria, Acute Intermittent (enzymology, genetics, prevention & control, therapy) Protein Folding

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