A Pharmacological Chaperone Therapy for Acute Intermittent Porphyria.

Autor:	Bustad HJ; Department of Biomedicine, University of Bergen, 5020 Bergen, Norway., Toska K; Norwegian Porphyria Centre (NAPOS), Laboratory for Clinical Biochemistry, Haukeland University Hospital, 5021 Bergen, Norway., Schmitt C; Assistance Publique Hôpitaux de Paris (AP-HP), Centre Français des Porphyries, Hôpital Louis Mourier, 92700 Colombes, France; INSERM U1149, Center for Research on Inflammation (CRI), Université de Paris, 75018 Paris, France., Vorland M; Norwegian Porphyria Centre (NAPOS), Laboratory for Clinical Biochemistry, Haukeland University Hospital, 5021 Bergen, Norway., Skjærven L; Department of Biomedicine, University of Bergen, 5020 Bergen, Norway., Kallio JP; Department of Biomedicine, University of Bergen, 5020 Bergen, Norway., Simonin S; Assistance Publique Hôpitaux de Paris (AP-HP), Centre Français des Porphyries, Hôpital Louis Mourier, 92700 Colombes, France; INSERM U1149, Center for Research on Inflammation (CRI), Université de Paris, 75018 Paris, France., Letteron P; INSERM U1149, Center for Research on Inflammation (CRI), Université de Paris, 75018 Paris, France., Underhaug J; Department of Chemistry, University of Bergen, 5020 Bergen, Norway., Sandberg S; Norwegian Porphyria Centre (NAPOS), Laboratory for Clinical Biochemistry, Haukeland University Hospital, 5021 Bergen, Norway; Department of Global Public Health and Primary Care, University of Bergen, 5020 Bergen, Norway; The Norwegian Quality Improvement of Primary Care Laboratories, Haraldsplass Deaconess Hospital, 5009 Bergen, Norway., Martinez A; Department of Biomedicine, University of Bergen, 5020 Bergen, Norway. Electronic address: aurora.martinez@uib.no.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2020 Feb 05; Vol. 28 (2), pp. 677-689. Date of Electronic Publication: 2019 Dec 04.
DOI:	10.1016/j.ymthe.2019.11.010
Abstrakt:	Mutations in hydroxymethylbilane synthase (HMBS) cause acute intermittent porphyria (AIP), an autosomal dominant disease where typically only one HMBS allele is mutated. In AIP, the accumulation of porphyrin precursors triggers life-threatening neurovisceral attacks and at long-term, entails an increased risk of hepatocellular carcinoma, kidney failure, and hypertension. Today, the only cure is liver transplantation, and a need for effective mechanism-based therapies, such as pharmacological chaperones, is prevailing. These are small molecules that specifically stabilize a target protein. They may be developed into an oral treatment, which could work curatively during acute attacks, but also prophylactically in asymptomatic HMBS mutant carriers. With the use of a 10,000 compound library, we identified four binders that further increased the initially very high thermal stability of wild-type HMBS and protected the enzyme from trypsin digestion. The best hit and a selected analog increased steady-state levels and total HMBS activity in human hepatoma cells overexpressing HMBS, and in an Hmbs-deficient mouse model with a low-expressed wild-type-like allele, compared to untreated controls. Moreover, the concentration of porphyrin precursors decreased in liver of mice treated with the best hit. Our findings demonstrate the great potential of these hits for the development of a pharmacological chaperone-based corrective treatment of AIP by enhancing wild-type HMBS function independently of the patients' specific mutation. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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