Mechanistic modelling of enzyme-restoration effects of new recombinant liver-targeted proteins in acute intermittent porphyria
Background and Purpose:Acute intermittent porphyria (AIP) is a rare disease causedby a genetic mutation in the hepatic activity of the porphobilinogen-deaminase. Weaimed to develop a mechanistic model of the enzymatic restoration effects of a noveltherapy based on the administration of different for...
| Autores: | , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/65793 |
| Acceso en línea: | https://hdl.handle.net/10171/65793 |
| Access Level: | acceso abierto |
| Palabra clave: | Acute intermittent porphyria AIP Mechanistic Modelling Porphobilinogen deaminase |
| Sumario: | Background and Purpose:Acute intermittent porphyria (AIP) is a rare disease causedby a genetic mutation in the hepatic activity of the porphobilinogen-deaminase. Weaimed to develop a mechanistic model of the enzymatic restoration effects of a noveltherapy based on the administration of different formulations of recombinanthuman-PBGD (rhPBGD) linked to the ApoAI lipoprotein. This fusion protein circu-lates in blood, incorporating into HDL and penetrating hepatocytes.Experimental Approach:Single i.v. dose of different formulations of rhPBGD linkedto ApoAI were administered to AIP mice in which a porphyric attack was triggered byi.p. phenobarbital. Data consist on 24 h urine excreted amounts of heme precursors,5-aminolevulinic acid (ALA), PBG and total porphyrins that were analysed using non-linear mixed-effects analysis.Key Results:The mechanistic model successfully characterized over time theamounts excreted in urine of the three heme precursors for different formulations ofrhPBGD and unravelled several mechanisms in the heme pathway, such as the regu-lation in ALA synthesis by heme. Treatment with rhPBGD formulations restoredPBGD activity, increasing up to 51 times the value of the rate of tPOR formationestimated from baseline. Model-based simulations showed that several formulationprototypes provided efficient protective effects when administered up to 1 weekprior to the occurrence of the AIP attack.Conclusion and Implications:The model developed had excellent performance overa range of doses and formulation type. This mechanistic model warrants use beyondApoAI-conjugates and represents a useful tool towards more efficient drug treat-ments of other enzymopenias as well as for acute intermittent porphyria. |
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