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

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 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.

Keywords: acute intermittent porphyria; enzyme intermediates; haem; hydroxymethylbilane synthase; pharmacological chaperones; porphobilinogen deaminase; protein stabilisation; proteostasis regulators; pyrrole chain elongation.

Figure 3

The pyrrole chain elongation catalysed by hydroxymethylbilane synthase. Hydroxymethylbilane synthase (HMBS) and the pyrrole chain elongation. (a) Cartoon representation of HMBS crystal structure (blue; PDB ID: 3ECR) with the dipyrromethane (DPM) cofactor in the centre. The housekeeping HMBS is a monomeric protein of 39.3 KDa. (b) HMBS (blue) with the DPM cofactor (2 × PBG molecules; green) constitute the holoenzyme (E) and bind four PBG substrates (S; red), sequentially, producing enzyme intermediates ES (=ES₁), ES₂, ES₃ and ES₄. Hydroxymethylbilane (HMB), the linear tetrapyrrole product, is released by hydrolysis. The substrate sidechains are acetate (A) and propionate (P). Figure modified from [76,77].

Figure 1

The haem biosynthetic pathway and associated porphyria disorders. In mammals, haem is synthesised in all nucleated cells through eight enzymatic steps and is essential for life. Each of the porphyrias (orange boxes) is caused by partial deficiency of the associated haem biosynthesis enzyme (green boxes), except for X-linked erythropoietic protoporphyria (XLEPP), which is caused by gain-of-function mutations of the erythroid-specific δ-aminolaevulinic acid synthase 2 (ALAS2) gene. ALAS1, the housekeeping enzyme, is expressed in all other tissues. ALAS1 is under negative feedback control by haem (dashed blue line, left) and is rate-limiting under normal circumstances, when the catalytic capacities of the other enzymes in the pathway are normal. Drugs and hormonal factors have been identified as the most common precipitating factors for an acute attack (dashed red lines and sites of impact) [6]. Non-enzymatic and spontaneous cyclisation of hydroxymethylbilane to uroporphyrinogen I is an alternative path in cases of deficient uroporphyrinogen III synthase activity (dashed blue line, right). Figure modified from [7,8].

Figure 2

Overview of the action sites of established and potential therapy options for AIP. With a defect HMBS enzyme, ALA and PBG, produced in excess by the liver, leak into the bloodstream, and subsequently the nervous system. Therapeutic options that inhibit the pathway and/or accumulation of ALA and PBG are indicated in red, whereas options that enhance HMBS activity are shown in blue. Glucose treatment and RNAi therapy affect the ALAS1 gene expression, ultimately downregulating the haem biosynthesis. Haem infusions inhibit the haem biosynthesis by negative feedback on ALAS1. Gene replacement therapy and mRNA therapeutics aid in delivering normal HMBS capacity and pharmacological chaperones aid in the expression of the HMBS protein or help the already-expressed HMBS protein to function correctly. Enzyme replacement therapy aims to supply functional HMBS to deplete surplus amounts of ALA and PBG. Figure modified from [9].

Figure 4

Overview of reported HMBS variants. The numbers are based on 517 variants included in the 2020.3 Human Gene Mutation Database (HGMD^®; www.hgmd.cf.ac.uk/ac/gene.php?gene=HMBS) and the variants are grouped into different mutation types. The category ‘Other’ includes small indels, 2.7%; regulatory, 1.4%; gross insertions/duplications, 0.8%; complex rearrangements, 0.6%.