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mRNA-based therapy in a rabbit model of variegate porphyria offers new insights into the pathogenesis of acute attacks. | LitMetric

AI Article Synopsis

  • Variegate porphyria (VP) is caused by a deficiency in the enzyme protoporphyrinogen oxidase, leading to clinical issues without a clear animal model for study.
  • In experiments with rabbits, a combination of two drugs resulted in increased toxic heme precursor levels, causing a range of health issues including hypertension and impaired motor function.
  • Administering porphobilinogen deaminase mRNA improved enzyme activity and normalized harmful substance levels, suggesting that enhancing this enzyme's function is key to mitigating acute VP attacks.

Article Abstract

Variegate porphyria (VP) results from haploinsufficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in the heme synthesis pathway. There is no VP model that recapitulates the clinical manifestations of acute attacks. Combined administrations of 2-allyl-2-isopropylacetamide and rifampicin in rabbits halved hepatic PPOX activity, resulting in increased accumulation of a potentially neurotoxic heme precursor, lipid peroxidation, inflammation, and hepatocyte cytoplasmic stress. Rabbits also showed hypertension, motor impairment, reduced activity of critical mitochondrial hemoprotein functions, and altered glucose homeostasis. Hemin treatment only resulted in a slight drop in heme precursor accumulation but further increased hepatic heme catabolism, inflammation, and cytoplasmic stress. Hemin replenishment did protect against hypertension, but it failed to restore action potentials in the sciatic nerve or glucose homeostasis. Systemic porphobilinogen deaminase (PBGD) mRNA administration increased hepatic PBGD activity, the third enzyme of the pathway, and rapidly normalized serum and urine porphyrin precursor levels. All features studied were improved, including those related to critical hemoprotein functions. In conclusion, the VP model recapitulates the biochemical characteristics and some clinical manifestations associated with severe acute attacks in humans. Systemic PBGD mRNA provided successful protection against the acute attack, indicating that PBGD, and not PPOX, was the critical enzyme for hepatic heme synthesis in VP rabbits.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368795PMC
http://dx.doi.org/10.1016/j.omtn.2021.05.010DOI Listing

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