Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution

Abstract

Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by the hepatic deficiency of porphobilinogen deaminase (PBGD) and the slowdown of heme biosynthesis. AIP symptomatology includes life-threatening, acute neurovisceral or neuropsychiatric attacks manifesting in response to precipitating factors. The latter promote the upregulation of 5-aminolevulinic acid synthase-1 (ALAS1), the first enzyme of heme biosynthesis, which promotes the overload of neurotoxic porphyrin precursors. Hemin or glucose infusions are the first-line therapies for the reduction of ALAS1 levels in patients with mild to severe AIP, while liver transplantation is the only curative treatment for refractory patients. Recently, the RNA-interference against ALAS1 was approved as a treatment for adult and adolescent patients with AIP. These emerging therapies aim to substitute dysfunctional PBGD with adeno-associated vectors for genome editing, human PBGD mRNA encapsulated in lipid nanoparticles, or PBGD protein linked to apolipoprotein A1. Finally, the impairment of glucose metabolism linked to insulin resistance, and mitochondrial aberrations during AIP pathophysiology provided new therapeutic targets. Therefore, the use of liver-targeted insulin and insulin-mimetics such as α-lipoic acid may be useful for overcoming metabolic dysfunction in these subjects. Herein, the present review aims to provide an overview of AIP pathophysiology and management, focusing on conventional and recent therapeutical approaches.

Keywords: AIP; PBGD; heme; insulin; liver metabolism; α-lipoic acid.

Figure 1

The heme biosynthetic pathway and AIP pathophysiology. Heme biosynthesis begins in mitochondria with the conversion of glycine and succinyl-CoA to δ-aminolevulinic acid (ALA) through the δ-aminolevulinic acid synthase-1 (ALAS1) enzyme. In the cytoplasm, ALA is metabolized to porphobilinogen (PBG) and then to COPROgen III. The latter is then transported into mitochondria for the synthesis of heme, which in turn downregulates ALAS1. The deficiency of HMBS genes causes a reduction in hepatic heme synthesis, leading to the stopping of its negative feedback on ALAS1. Thereby, the levels of porphyrin precursors (ALA and PBG), mainly in response to precipitating factors, may accumulate in the liver, systemic circulation, and urine, triggering neurological damage.

Figure 2

A schematic overview of the current and ongoing efforts in the treatment of AIP and their therapeutical targets. In the white boxes, hemin, glucose, liver transplantation, and the recently approved givosiran represent the standard treatments for AIP management. Therapies under development are in peach-pink and include AAV5-hPBGD gene therapy, hPBGD-mRNA delivered by LNPs, and liver-targeted rhApoA1-PBGD. Finally, special attention should be given to insulin and insulin-sensitizers (light green) as potential alternative strategies for the correction of metabolic dysfunction and the enhancement of glucose therapy.