Functional brain changes in acute hepatic porphyrias has been described in various experimental models. However, direct evidence linking neurological alterations to hepatic porphobilinogen deaminase (PBGD) deficiency, the recurrence of acute attacks, or their potential reversion in response to available therapies is lacking. Given the limited availability of patients eligible for clinical studies in rare disorders such as acute intermittent porphyria (AIP), physiopathological information from relevant animal models is of paramount importance for improving clinical trial design and endpoints assessment. In this work, we replicated AIP in adult non-human primates (NHPs) through selective knockdown of the hepatic PBGD gene. Our aim was to asses neural GABAergic activity and glucose metabolism in the brain of these animals before and after the induction of AIP, as well as after the administration of current and emerging therapies.

The benzodiazepine receptor antagonist flumazenil binds to the benzodiazepine binding site of γ-aminobutyric acid-type A (GABAA) receptors, which are the most prominent inhibitory neurotransmitter receptor in the central nervous system (CNS). Flumazenil can bind GABA receptors that are not activated by GABA, providing a surrogate index for assessing the activation status of these receptor in the brain. At baseline, PET/CT imaging revealed a prominent distribution of the radiotracer [¹¹C]flumazenil in the brain cortex and hippocampus. A significant reduction of [¹¹C]-flumazenil uptake was observed in the brain of AIP NHPs, starting one month after AIP induction. Reduced uptake remained consistent following recurrent attacks in untreated animals, whereas multi-dose administration of hPBGD mRNA uniformly restored baseline uptake across all regions.

The prefrontal motor cortex and subcortical ganglia at the brain’s base, which are associated with movement initiation and planning, showed the highest uptake of the glucose radiotracer [¹⁸F]-fluorodeoxyglucose ([¹⁸F]FDG). Induction of AIP in NHPs led to a notable reduction in the radiotracer signal, further declining with repeated attacks. Notably, treatment with hPBGD mRNA significantly improved brain [¹⁸F]FDG uptake and restored baseline levels.

In conclusion, our novel clinically relevant AIP model confirmed alterations in glucose uptake and GABAergic activity in the brain. Importantly, since PBGD expression in our model is specifically impaired only in the liver, our findings represent the first experimental demonstration of the hepatic origin of the functional alterations observed in the CNS of AIP patients.