Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment

Abstract

Rare diseases, especially monogenic diseases, which usually affect a single target protein, have attracted growing interest in drug research by encouraging pharmaceutical companies to design and develop therapeutic products to be tested in the clinical arena. Acute intermittent porphyria (AIP) is one of these rare diseases. AIP is characterized by haploinsufficiency in the third enzyme of the heme biosynthesis pathway. Identification of the liver as the target organ and a detailed molecular characterization have enabled the development and approval of several therapies to manage this disease, such as glucose infusions, heme replenishment, and, more recently, an siRNA strategy that aims to down-regulate the key limiting enzyme of heme synthesis. Given the involvement of hepatic hemoproteins in essential metabolic functions, important questions regarding energy supply, antioxidant and detoxifying responses, and glucose homeostasis remain to be elucidated. This review reports recent insights into the pathogenesis of acute attacks and provides an update on emerging treatments aimed at increasing the activity of the deficient enzyme in the liver and restoring the physiological regulation of the pathway. While further studies are needed to optimize gene therapy vectors or large-scale production of liver-targeted PBGD proteins, effective protection of PBGD mRNA against the acute attacks has already been successfully confirmed in mice and large animals, and mRNA transfer technology is being tested in several clinical trials for metabolic diseases.

Acute Intermittent Porphyria’s Symptoms and Management: A Narrative Review

“…Besides the aforementioned established treatment options, there are several newly emerging innovative treatment modalities, which are part of experimental studies. In this review, we will mainly focus on recombinant enzyme replacement and adeno-associated virus (AAV)-mediated gene therapy (GT) and explain the role of chaperones and (PBGD) mRNA [ 42 ].…”

“…One very promising and frequently discussed idea is the application of PBGD messenger (m) RNA [ 42 ]. mRNAs are small single-stranded molecules of RNA, which are used by ribosomes as templates for protein synthesis.…”

“…To increase the function and availability of PBGD, it may be possible to “deliver” the cell with physiologic PBGD mRNA externally. The cells are able to internalize PBGD mRNA, if it is carried in the form of nanoliposomes [ 42 ]. This idea was tested out by a study group on mice and nonhuman primate collectives with very promising results [ 42 , 43 ].…”

“…The cells are able to internalize PBGD mRNA, if it is carried in the form of nanoliposomes [ 42 ]. This idea was tested out by a study group on mice and nonhuman primate collectives with very promising results [ 42 , 43 ].…”

“…Another field of current research is adeno-associated virus (AAV)-mediated gene therapy (GT) [ 42 ]. The goal of gene therapy is to create a long-term solution for the disease by directly focusing on where the pathology of AIP arises.…”