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dc.contributor.authorBustad, Helene J.en_US
dc.contributor.authorToska, Karenen_US
dc.contributor.authorSchmitt, Carolineen_US
dc.contributor.authorVorland, Martaen_US
dc.contributor.authorSkjærven, Larsen_US
dc.contributor.authorKallio, Juha Pekkaen_US
dc.contributor.authorSimonin, Sylvieen_US
dc.contributor.authorLettéron, Philippeen_US
dc.contributor.authorUnderhaug, Jarlen_US
dc.contributor.authorSandberg, Sverreen_US
dc.contributor.authorMartinez, Auroraen_US
dc.PublishedBustad HJ, Toska K, Schmitt C, Vorland M, Skjærven L, Kallio J, Simonin, Lettéron P, Underhaug J, Sandberg S, Martinez A. A Pharmacological Chaperone Therapy for Acute Intermittent Porphyria. Molecular Therapy. 2019eng
dc.description.abstractMutations 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.en_US
dc.rightsAttribution CC BY-NC-ND 4.0eng
dc.titleA Pharmacological Chaperone Therapy for Acute Intermittent Porphyriaen_US
dc.typePeer reviewed
dc.typeJournal article
dc.rights.holderCopyright 2019 The Author(s)
dc.source.journalMolecular Therapy
dc.relation.projectHelse Vest RHF: 912246
dc.relation.projectNorges forskningsråd: 285295
dc.relation.projectNorges forskningsråd: 261826
dc.relation.projectNorges forskningsråd: 245922

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Attribution CC BY-NC-ND 4.0
Except where otherwise noted, this item's license is described as Attribution CC BY-NC-ND 4.0