Variegate porphyria (VP) results from haploinsufficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in the heme synthesis pathway. It is characterized by skin photosensitivity and neurological acute attacks caused by strong accumulation of porphyrins and porphyrin precursors, respectively. No model recapitulates clinical manifestations of variegate porphyria.

The aim of this study was to characterize a novel model of chemically-induced VP in rabbits. Combined administration of 2-allyl-2-isopropylacetamide and rifampicin halved hepatic PPOX activity and reproduced the biochemical derangements associated to acute attacks found in patients, and induced hypertension, altered glucose homeostasis, motor impairment and reduced activity of critical hemeprotein functions. Rapid expression of therapeutic proteins can be achieved hours after systemic administration of messenger RNAs (mRNA), representing an etiological solution for acute decompensations. 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 associated with acute attack were improved, including those related to critical mitochondrial hemoprotein functions. Finally, multiple administrations protected against hypertension, altered glucose homeostasis and motor impairment.

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.