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Prospect and progress of gene therapy in acute intermittent porphyria

ABSTRACT Introduction: Acute Intermittent porphyria (AIP) is a rare autosomal dominant disease caused by mutations in the gene encoding hydroxymethylbilane synthase (HMBS), previously called porphobilinogen deaminase (PBGD), the third enzyme in the heme synthesis pathway. Activation of the first enzyme of this pathway, delta-aminolevulinic acid synthase-1 (ALAS1) in the context of porphobilinogen deaminase (PBGD) deficiency leads to accumulation of the neurotoxic molecules, aminolevulinic acid (ALA) and porphobilinogen (PBG), and precipitates acute porphyria attacks. The fact that liver transplantation resolves the disease indicates that gene-complementation or gene-silencing approaches targeting the hepatocytes might correct or attenuate the biochemical and clinical manifestations of AIP. Areas covered: Remarkable progress has been made in the development of genetic treatments for AIP, in particular the use of gene transfer vectors such as AAV-based vectors to introduce the therapeutic gene into hepatocytes or the administration of short interfering RNA (siRNA) molecules to inhibit ALAS1 expression. This review will provide an overview of the current status of these therapeutic strategies. Expert opinion: Although the effectiveness of gene therapy has yet to be proven more extensively, the results obtained from patients with other inherited diseases who have received genetic complementation therapy and the encouraging data obtained with siRNA invites optimism. However, in AIP, despite promising preliminary results, several scientific obstacles remain to be solved and additional clinical data are required before either approach becomes a reality.