International Journal of Molecular Sciences Review Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators Helene J. Bustad 1 , Juha P. Kallio 1 , Marta Vorland 2, Valeria Fiorentino 3 , Sverre Sandberg 2,4, Caroline Schmitt 3,5, Aasne K. Aarsand 2,4,* and Aurora Martinez 1,* 1 Department of Biomedicine, University of Bergen, 5020 Bergen, Norway; [email protected] (H.J.B.); [email protected] (J.P.K.) 2 Norwegian Porphyria Centre (NAPOS), Department for Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5021 Bergen, Norway; [email protected] (M.V.); [email protected] (S.S.) 3 INSERM U1149, Center for Research on Inflammation (CRI), Université de Paris, 75018 Paris, France; valeria.fi[email protected] (V.F.); [email protected] (C.S.) 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 * Correspondence: [email protected] (A.K.A.); [email protected] (A.M.) Abstract: 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 Citation: Bustad, H.J.; Kallio, J.P.; and accumulation of toxic haem precursors in the liver. Clinically, this presents as acute attacks Vorland, M.; Fiorentino, V.; Sandberg, characterised by severe abdominal pain and a wide array of neurological and psychiatric symptoms, S.; Schmitt, C.; Aarsand, A.K.; and, in the long-term setting, the development of primary liver cancer, hypertension and kidney Martinez, A. Acute Intermittent Porphyria: An Overview of Therapy failure. Treatment options are few, and therapies preventing the development of symptomatic disease Developments and Future and long-term complications are non-existent. Here, we provide an overview of the disorder and Perspectives Focusing on Stabilisation treatments already in use in clinical practice, in addition to other therapies under development or in of HMBS and Proteostasis Regulators. the pipeline. We also introduce the pathomechanistic effects of HMBS mutations, and present and Int. J. Mol. Sci. 2021, 22, 675. discuss emerging therapeutic options based on HMBS stabilisation and the regulation of proteostasis. https://doi.org/10.3390/ijms22020675 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 Received: 21 November 2020 promising for upcoming patient-tailored interventions in AIP. Accepted: 4 January 2021 Published: 12 January 2021 Keywords: acute intermittent porphyria; haem; hydroxymethylbilane synthase; enzyme intermedi- ates; pyrrole chain elongation; porphobilinogen deaminase; pharmacological chaperones; protein Publisher’s Note: MDPI stays neu- stabilisation; proteostasis regulators tral with regard to jurisdictional clai- ms in published maps and institutio- nal affiliations. 1. Introduction The porphyrias are a heterogeneous group of rare, inherited inborn errors of metabolism Copyright: © 2021 by the authors. Li- diseases, where each porphyria, except X-linked erythropoietic protoporphyria, results censee MDPI, Basel, Switzerland. from a partial deficiency in one of the eight enzymes of the haem biosynthetic pathway [1]. This article is an open access article The porphyrias can be classified as acute and/or cutaneous, depending on their clinical distributed under the terms and con- presentation (Figure1). The most prevalent acute porphyria is acute intermittent porphyria ditions of the Creative Commons At- (AIP), an autosomal dominant disease with low clinical penetrance, caused by deficiency tribution (CC BY) license (https:// in the third enzyme of the haem biosynthesis, hydroxymethylbilane synthase (HMBS). AIP creativecommons.org/licenses/by/ 4.0/). is characterised by the overproduction of toxic haem precursors in the liver, resulting in Int. J. Mol. Sci. 2021, 22, 675. https://doi.org/10.3390/ijms22020675 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 28 Int. J. Mol. Sci. 2021, 22, 675 (HMBS). AIP is characterised by the overproduction of toxic haem precursors in the liver,2 of 25 resulting in so-called acute attacks, presenting with severe abdominal pain and a wide array of neurological and psychiatric symptoms. AIP is also associated with long-term complicationsso-called acute in attacks,the form presenting of primary with liver severe cancer, abdominal hypertension, pain and and kidney a wide failure array of [2–4]. neu- Thererological are andfew psychiatricestablished symptoms.treatment options, AIP is also with associated a complete with lack long-term of therapies complications that pre- ventin the the form development of primary of liver symptomatic cancer, hypertension, disease and long-term and kidney complications failure [2–4]. in There susceptible are few HMBSestablished mutation treatment carriers. options, Thus, patients with a complete with AIP lack and of genetically therapies thatpredisposed prevent theindividuals develop- mustment adhere of symptomatic to lifelong disease lifestyle and measures long-term to reduce complications their risk in of susceptible symptomaticHMBS diseasemutation [5]. Fromcarriers. a mechanistic Thus, patients point with of view, AIP andthere genetically are, however, predisposed many differen individualst potential must treatment adhere to optionslifelong for lifestyle AIP. In measures this review, to reduce we provide their risk an of overview symptomatic of established disease [5 ].approaches, From a mecha- the statusnistic of point relevant of view, therapy, there are,primarily however, gene-r manyelated, different developments, potential treatmentand emerging options therapeu- for AIP. ticIn options, this review, focusing we provide on HMBS an overviewstabilisation of establishedand the regulation approaches, of proteostasis the status (Figure of relevant 2). Wetherapy, will also primarily discuss gene-related, the current developments,structural information and emerging on wild-type therapeutic HMBS options, and disease- focusing associatedon HMBS variants, stabilisation partly and aiding the regulation in envisioning of proteostasis the complex (Figure kinetics2). We of will this alsoenzyme, discuss as wellthe currentas information structural gaps information that hinder on a wild-typecomplete understanding HMBS and disease-associated of the oligopyrrole variants, elon- gationpartly mechanism. aiding in envisioning the complex kinetics of this enzyme, as well as information gaps that hinder a complete understanding of the oligopyrrole elongation mechanism. FigureFigure 1. The haemhaembiosynthetic biosynthetic pathway pathway and and associated associated porphyria porphyria disorders. disorders. In mammals, In mammals, haem is haem synthesised is synthesised in all nucleated in all nucleatedcells through cells eightthrough enzymatic eight enzymatic steps and steps is essential and is essential for life. Eachfor life. of Each the porphyrias of the porphyrias (orange (orange boxes) isboxes) caused is caused by partial by partialdeficiency deficiency of the associatedof the associated haem biosynthesishaem biosynthesis enzyme enzyme (green (green boxes), boxes), except exce forpt X-linked for X-linked erythropoietic erythropoietic protoporphyria protopor- phyria(XLEPP), (XLEPP), which iswhich caused is caused by gain-of-function by gain-of-fu mutationsnction mutations of the erythroid-specific of the erythroid-specificd-aminolaevulinic δ-aminolaevulinic acid synthase acid synthase 2 (ALAS2 2 ) (gene.ALAS2 ALAS1,) gene. theALAS1, housekeeping the housekeeping enzyme, enzyme, is expressed is expressed in all other in tissues.all other ALAS1 tissues. is ALAS1 under negativeis underfeedback negative controlfeedback by controlhaem (dashed by haem blue (dashed line, left)blue andline, is left) rate-limiting and is rate-limiting under normal under circumstances, normal circumstances, when the when catalytic the capacitiescatalytic capacities of the other of the other enzymes in the pathway are normal. Drugs and hormonal factors have been identified as the most common enzymes in the pathway are normal. Drugs and hormonal factors have been identified as the most common precipitating precipitating factors for an acute attack (dashed red lines and sites of impact) [6]. Non-enzymatic and spontaneous cy- factors for an acute attack (dashed red lines and sites of impact) [6]. Non-enzymatic and spontaneous cyclisation of clisation of hydroxymethylbilane to uroporphyrinogen I is an alternative path in cases of deficient uroporphyrinogen III hydroxymethylbilane to uroporphyrinogen I is an alternative path in cases of deficient uroporphyrinogen III synthase synthase activity (dashed blue line, right). Figure modified from [7] and [8]. activity (dashed blue line, right). Figure modified from [7,8]. Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 28 Int. J. Mol. Sci. 2021, 22, 675 3 of 25 FigureFigure 2. Overview 2. Overview