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Review

Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators

1
Department of Biomedicine, University of Bergen, 5020 Bergen, Norway
2
Norwegian Porphyria Centre (NAPOS), Department for Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5021 Bergen, Norway
3
INSERM U1149, Center for Research on Inflammation (CRI), Université de Paris, 75018 Paris, France
4
Norwegian Organization for Quality Improvement of Laboratory Examinations (Noklus), Haraldsplass Deaconess Hospital, 5009 Bergen, Norway
5
Assistance Publique Hôpitaux de Paris (AP-HP), Centre Français des Porphyries, Hôpital Louis Mourier, 92700 Colombes, France
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(2), 675; https://doi.org/10.3390/ijms22020675
Received: 21 November 2020 / Revised: 2 January 2021 / Accepted: 4 January 2021 / Published: 12 January 2021
Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease with low clinical penetrance, caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes the third enzyme in the haem biosynthesis pathway. In susceptible HMBS mutation carriers, triggering factors such as hormonal changes and commonly used drugs induce an overproduction and accumulation of toxic haem precursors in the liver. Clinically, this presents as acute attacks characterised by severe abdominal pain and a wide array of neurological and psychiatric symptoms, and, in the long-term setting, the development of primary liver cancer, hypertension and kidney failure. Treatment options are few, and therapies preventing the development of symptomatic disease and long-term complications are non-existent. Here, we provide an overview of the disorder and treatments already in use in clinical practice, in addition to other therapies under development or in the pipeline. We also introduce the pathomechanistic effects of HMBS mutations, and present and discuss emerging therapeutic options based on HMBS stabilisation and the regulation of proteostasis. These are novel mechanistic therapeutic approaches with the potential of prophylactic correction of the disease by totally or partially recovering the enzyme functionality. The present scenario appears promising for upcoming patient-tailored interventions in AIP. View Full-Text
Keywords: acute intermittent porphyria; haem; hydroxymethylbilane synthase; enzyme intermediates; pyrrole chain elongation; porphobilinogen deaminase; pharmacological chaperones; protein stabilisation; proteostasis regulators acute intermittent porphyria; haem; hydroxymethylbilane synthase; enzyme intermediates; pyrrole chain elongation; porphobilinogen deaminase; pharmacological chaperones; protein stabilisation; proteostasis regulators
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MDPI and ACS Style

Bustad, H.J.; Kallio, J.P.; Vorland, M.; Fiorentino, V.; Sandberg, S.; Schmitt, C.; Aarsand, A.K.; Martinez, A. Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators. Int. J. Mol. Sci. 2021, 22, 675. https://doi.org/10.3390/ijms22020675

AMA Style

Bustad HJ, Kallio JP, Vorland M, Fiorentino V, Sandberg S, Schmitt C, Aarsand AK, Martinez A. Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators. International Journal of Molecular Sciences. 2021; 22(2):675. https://doi.org/10.3390/ijms22020675

Chicago/Turabian Style

Bustad, Helene J., Juha P. Kallio, Marta Vorland, Valeria Fiorentino, Sverre Sandberg, Caroline Schmitt, Aasne K. Aarsand, and Aurora Martinez. 2021. "Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators" International Journal of Molecular Sciences 22, no. 2: 675. https://doi.org/10.3390/ijms22020675

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