Recombinant porphobilinogen deaminase targeted to the liver corrects enzymopenia in a mouse model of acute intermittent porphyria

Correction of enzymatic deficits in hepatocytes by systemic administration of a recombinant protein is a desired therapeutic goal for hepatic enzymopenic disorders such as acute intermittent porphyria (AIP), an inherited porphobilinogen deaminase (PBGD) deficiency. Apolipoprotein A-I (ApoAI) is inte...

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Published in:Science translational medicine 2022-01, Vol.14 (627), p.eabc0700-eabc0700
Main Authors: Córdoba, Karol M, Serrano-Mendioroz, Irantzu, Jericó, Daniel, Merino, María, Jiang, Lei, Sampedro, Ana, Alegre, Manuel, Corrales, Fernando, Garrido, María J, Martini, Paolo G V, Lanciego, José Luis, Prieto, Jesús, Berraondo, Pedro, Fontanellas, Antonio
Format: Article
Language:English
Subjects:
Animal models
Apolipoprotein A
Apolipoprotein A-I
Blood-brain barrier
Cholesterol
Enzymatic activity
Hepatocytes
High density lipoprotein
Hydroxymethylbilane synthase
Intravenous administration
Liver
Phenobarbital
Porphyria
Proteins
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Summary:Correction of enzymatic deficits in hepatocytes by systemic administration of a recombinant protein is a desired therapeutic goal for hepatic enzymopenic disorders such as acute intermittent porphyria (AIP), an inherited porphobilinogen deaminase (PBGD) deficiency. Apolipoprotein A-I (ApoAI) is internalized into hepatocytes during the centripetal transport of cholesterol. Here, we generated a recombinant protein formed by linking ApoAI to the amino terminus of human PBGD (rhApoAI-PBGD) in an attempt to transfer PBGD into liver cells. In vivo experiments showed that, after intravenous injection, rhApoAI-PBGD circulates in blood incorporated into high-density lipoprotein (HDL), penetrates into hepatocytes, and crosses the blood-brain barrier, increasing PBGD activity in both the liver and brain. Consistently, the intravenous administration of rhApoAI-PBGD or the hyperfunctional rApoAI-PBGD-I129M/N340S (rApoAI-PBGDms) variant efficiently prevented and abrogated phenobarbital-induced acute attacks in a mouse model of AIP. One month after a single intravenous dose of rApoAI-PBGDms, the protein was still detectable in the liver, and hepatic PBGD activity remained increased above control values. A long-lasting therapeutic effect of rApoAI-PBGDms was observed after either intravenous or subcutaneous administration. These data describe a method to deliver PBGD to hepatocytes with resulting enhanced hepatic enzymatic activity and protection against AIP attacks in rodent models, suggesting that the approach might be an effective therapy for AIP.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/scitranslmed.abc0700