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Emerging therapies for acute intermittent porphyria

Published online by Cambridge University Press:  02 November 2016

Antonio Fontanellas ,
Matías A. Ávila  and
Pedro Berraondo
Antonio Fontanellas*
Affiliation:
Hepatology Area, Centre for Applied Medical Research, University of Navarra, Spain Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain CIBEREHD, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain
Matías A. Ávila
Affiliation:
Hepatology Area, Centre for Applied Medical Research, University of Navarra, Spain Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain CIBEREHD, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain
Pedro Berraondo
Affiliation:
Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain Immunology Area, Centre for Applied Medical Research, University of Navarra, Spain
*
*Corresponding author:Antonio Fontanellas, PhD, Hepatology Area, Center for Applied Medical Research, Avda. Pio XII, 55–31008 Pamplona, Spain. E-mail: [email protected]
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Abstract

Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disease caused by hepatic deficiency of hydroxymethylbilane synthase (HMBS), the third enzyme of the heme synthesis pathway. The dominant clinical feature is acute neurovisceral attack associated with high production of potentially neurotoxic porphyrin precursors due to increased hepatic heme consumption. Current Standard of Care is based on a down-regulation of hepatic heme synthesis using heme therapy. Recurrent hyper-activation of the hepatic heme synthesis pathway affects about 5% of patients and can be associated with neurological and metabolic manifestations and long-term complications including chronic kidney disease and increased risk of hepatocellular carcinoma. Prophylactic heme infusion is an effective strategy in some of these patients, but it induces tolerance and its frequent application may be associated with thromboembolic disease and hepatic siderosis. Orthotopic liver transplantation is the only curative treatment in patients with recurrent acute attacks. Emerging therapies including replacement enzyme therapy or gene therapies (HMBS-gene transfer and ALAS1-gene expression inhibition) are being developed to improve quality of life, reduce the significant morbidity associated with current therapies and prevent late complications such as hepatocellular cancer or kidney failure in HMBS mutation carriers with long-standing high production of noxious heme precursors. Herein, we provide a critical digest of the recent literature on the topic and a summary of recently developed approaches to AIP treatment and their clinical implications.

Type
Invited Review
Information
Expert Reviews in Molecular Medicine , Volume 18 , 2016 , e17
Copyright
Copyright © Cambridge University Press 2016 

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