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.

KEYWORDS:

• Acute intermittent porphyria
• gene therapy
• siRNA
• Adenoassociated viral vectors

Article highlights

• Liver-directed gene therapy using different gene delivery vectors protects against phenotypic manifestations of acute porphyria attacks in an AIP murine model.

• Gene therapy of AIP patients with recombinant AAV5 vector carrying the HMBS gene resulted in an improvement in the clinical course of the disease and the quality of life of some patients, although, ALA & PBG levels in urine did not decrease.

• Vector genomes were detected in the liver of patients as late as one year after administration. The integration frequency was low and the use of the AAV vector appears to be safe as no integration into hepatocellular carcinoma-associated genes was observed.

• The development of more efficient vehicles for gene delivery to the liver or the administration of higher doses of the therapeutic vector is essential for clinical success of gene therapy in AIP patients.

• Silencing the expression of the key player in the heme synthesis pathway in the liver, ALAS1, using siRNA molecules prevented phenobarbital-induced accumulation of plasma and urinary ALA and PBG in AIP mice but, more importantly, reduced urinary ALA and PBG excretion in asymptomatic AIP carriers with high excretion of porphyrin precursors.

As heme is essential for life, careful and extensive assessment of potential secondary effects of inhibiting ALAS1 will be critical to define the safety profile of siRNA-based treatments.

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Acknowledgments

The authors thank the patients and hospital staff who participated in these studies. The authors are grateful to Dr Paul Wilson for critical revision of the manuscript and to Dr Mirja Hommel for correction of the manuscript.

Declaration of interest

The authors’ work presented in this review was partially supported by the European Community’s Seventh Framework Program FP7-Health-2010-261506 (AIPGENE). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.