Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution

Abstract

Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by the hepatic deficiency of porphobilinogen deaminase (PBGD) and the slowdown of heme biosynthesis. AIP symptomatology includes life-threatening, acute neurovisceral or neuropsychiatric attacks manifesting in response to precipitating factors. The latter promote the upregulation of 5-aminolevulinic acid synthase-1 (ALAS1), the first enzyme of heme biosynthesis, which promotes the overload of neurotoxic porphyrin precursors. Hemin or glucose infusions are the first-line therapies for the reduction of ALAS1 levels in patients with mild to severe AIP, while liver transplantation is the only curative treatment for refractory patients. Recently, the RNA-interference against ALAS1 was approved as a treatment for adult and adolescent patients with AIP. These emerging therapies aim to substitute dysfunctional PBGD with adeno-associated vectors for genome editing, human PBGD mRNA encapsulated in lipid nanoparticles, or PBGD protein linked to apolipoprotein A1. Finally, the impairment of glucose metabolism linked to insulin resistance, and mitochondrial aberrations during AIP pathophysiology provided new therapeutic targets. Therefore, the use of liver-targeted insulin and insulin-mimetics such as α-lipoic acid may be useful for overcoming metabolic dysfunction in these subjects. Herein, the present review aims to provide an overview of AIP pathophysiology and management, focusing on conventional and recent therapeutical approaches.

A case report of acute intermittent porphyria leading to severe disability

“…In the early stages of AIP episodes, when mild pain is present without severe clinical manifestations, glycogen loading therapy (300 g/day) can be utilized. It is crucial to note that large amounts of intravenous glucose may result in hemodilution, potentially exacerbating the risk of hyponatremia ( 48 ). Symptomatic supportive therapy is provided when other complications are present: opioid analgesics such as morphine and pethidine are relatively safe in acute episodes of abdominal pain; gabapentin and levetiracetam are recommended for patients with epileptic seizures; and for patients with severe hyponatremia, 3% hypertonic saline is administered via intravenous infusion ( 49 ).…”

Photodermatoses: what's new

“…The most common adverse effects of the drug were nausea and diarrhea and no major adverse effects were reported [26 ▪▪ ,27,28]. Perhaps even more promising are future therapeutics currently under development for AIP, including strategies aiming to substitute dysfunctional porphobilinogen deaminase (PBGD) with adeno-associated vectors for genome editing, human PBGD mRNA encapsulated in lipid nanoparticles, or PBGD protein linked to apolipoprotein A1 [29]. For example, Cordoba et al recently developed a recombinant PBGD protein that restored PBGD activity and heme biosynthesis in the liver and brain of a mouse model of AIP.…”

Acute Intermittent Porphyria’s Symptoms and Management: A Narrative Review

“…The current diagnostic methods include measuring elevated porphyrin levels in the serum, urine, and stool [ 11 , 12 ]. The genetic analysis of HMBS mutations is recommended for all patients [ 11 , 12 ].…”

“…For acute attacks, heme administration is recommended. Glucose may also be administered, if hemin is not readily available [ 11 , 12 ]. Heme prophylaxis can effectively control recurrence.…”

“…Heme prophylaxis can effectively control recurrence. The emergence of givosiran (hepatic ALAS1 targeting small interfering (si) RNA) represents great progress in treating AIP based on its etiology, and human porphobilinogen deaminase (hPBGD) messenger RNA (mRNA) is a promising treatment [ 11 , 12 ]. Liver transplantation is the last resort for patients with AIP [ 11 , 12 ].…”