Jericó-Asenjo, D. (Daniel)
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- mRNA-based therapy in a rabbit model of variegate porphyria offers new insights into the pathogenesis of acute attacks(2021) Alegre-Martinez, E. (Estibaliz); Martini, P. (Paolo); Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Avila, M.A. (Matías Antonio); Córdoba-Quiñones, K. M. (Karol Marcela); Martín, M. A. (Miguel A.); Oyarzabal, J. (Julen); Estella-Hermoso-de-Mendoza, A. (Ander); Schmitt, C. (Caroline); Santamaría, E. (Eva); Culerier, C. (Corinne); Fontanellas-Romá, A. (Antonio); Moran, M.A. (María Asunción); Gouya, L. (Laurent); Alegre-Esteban, M. (Manuel); Sampedro, A. (Ana); Jericó-Asenjo, D. (Daniel); Jiang, L. (Lei)Variegate porphyria (VP) results from haploinsufficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in the heme synthesis pathway. There is no VP model that recapitulates the clinical manifestations of acute attacks. Combined administrations of 2-allyl-2-isopropylacetamide and rifampicin in rabbits halved hepatic PPOX activity, resulting in increased accumulation of a potentially neurotoxic heme precursor, lipid peroxidation, inflammation, and hepatocyte cytoplasmic stress. Rabbits also showed hypertension, motor impairment, reduced activity of critical mitochondrial hemoprotein functions, and altered glucose homeostasis. Hemin treatment only resulted in a slight drop in heme precursor accumulation but further increased hepatic heme catabolism, inflammation, and cytoplasmic stress. Hemin replenishment did protect against hypertension, but it failed to restore action potentials in the sciatic nerve or glucose homeostasis. Systemic porphobilinogen deaminase (PBGD) mRNA administration increased hepatic PBGD activity, the third enzyme of the pathway, and rapidly normalized serum and urine porphyrin precursor levels. All features studied were improved, including those related to critical hemoprotein functions. In conclusion, the VP model recapitulates the biochemical characteristics and some clinical manifestations associated with severe acute attacks in humans. Systemic PBGD mRNA provided successful protection against the acute attack, indicating that PBGD, and not PPOX, was the critical enzyme for hepatic heme synthesis in VP rabbits.
- Nutritional Interventions with Bacillus coagulans Improved Glucose Metabolism and Hyperinsulinemia in Mice with Acute Intermittent Porphyria(2023) Riezu-Boj, J.I. (José Ignacio); Di-Pierro, E. (Elena); Collantes, M. (María); Moreno-Aliaga, M. J. (María Jesús); Peñuelas-Sanchez, I. (Ivan); Solares, I. (Isabel); Avila, M.A. (Matías Antonio); Córdoba-Quiñones, K. M. (Karol Marcela); Milagro-Yoldi, F.I. (Fermín Ignacio); Barajas, M. (Miguel); Dongiovanni, P. (Paola); Urtasun, R. (Raquel); Fontanellas-Romá, A. (Antonio); Longo, M. (Miriam); Sampedro, A. (Ana); Jericó-Asenjo, D. (Daniel)Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a mouse model of AIP that reproduces insulin resistance and altered glucose metabolism. The addition of spores of Bacillus coagulans in drinking water for 12 weeks modified the gut microbiome composition in AIP mice, ameliorated glucose tolerance and hyperinsulinemia, and stimulated fat disposal in adipose tissue. Lipid breakdown may be mediated by muscles burning energy and heat dissipation by brown adipose tissue, resulting in a loss of fatty tissue and improved lean/fat tissue ratio. Probiotic supplementation also improved muscle glucose uptake, as measured using Positron Emission Tomography (PET) analysis. In conclusion, these data provide a proof of concept that probiotics, as a dietary intervention in AIP, induce relevant changes in intestinal bacteria composition and improve glucose uptake and muscular energy utilization. Probiotics may offer a safe, efficient, and cost-effective option to manage people with insulin resistance associated with AIP.
- Mechanistic modelling of enzyme-restoration effects of new recombinant liver-targeted proteins in acute intermittent porphyria(Wiley, 2022) Parra-Guillen, Z.P. (Zinnia Patricia); Troconiz, I.F. (Iñaki F.); Córdoba, K.M. (Karol M.); Fontanellas-Romá, A. (Antonio); Vera-Yunca, D. (Diego); Jericó-Asenjo, D. (Daniel)Background and Purpose:Acute intermittent porphyria (AIP) is a rare disease causedby a genetic mutation in the hepatic activity of the porphobilinogen-deaminase. Weaimed to develop a mechanistic model of the enzymatic restoration effects of a noveltherapy based on the administration of different formulations of recombinanthuman-PBGD (rhPBGD) linked to the ApoAI lipoprotein. This fusion protein circu-lates in blood, incorporating into HDL and penetrating hepatocytes.Experimental Approach:Single i.v. dose of different formulations of rhPBGD linkedto ApoAI were administered to AIP mice in which a porphyric attack was triggered byi.p. phenobarbital. Data consist on 24 h urine excreted amounts of heme precursors,5-aminolevulinic acid (ALA), PBG and total porphyrins that were analysed using non-linear mixed-effects analysis.Key Results:The mechanistic model successfully characterized over time theamounts excreted in urine of the three heme precursors for different formulations ofrhPBGD and unravelled several mechanisms in the heme pathway, such as the regu-lation in ALA synthesis by heme. Treatment with rhPBGD formulations restoredPBGD activity, increasing up to 51 times the value of the rate of tPOR formationestimated from baseline. Model-based simulations showed that several formulationprototypes provided efficient protective effects when administered up to 1 weekprior to the occurrence of the AIP attack.Conclusion and Implications:The model developed had excellent performance overa range of doses and formulation type. This mechanistic model warrants use beyondApoAI-conjugates and represents a useful tool towards more efficient drug treat-ments of other enzymopenias as well as for acute intermittent porphyria.
- Brain ventricular enlargement in human and murine acute intermittent porphyria(2020) González-Aseguinolaza, G. (Gloria); D'Avola, D. (Delia); Benito, M. (Marina); Lanciego, J.L. (José Luis); Desco, M. (Manuel); Luis, E. (Elkin); Ortiz-de-Solorzano, C. (Carlos); Córdoba, K.M. (Karol M.); Fernández-Seara, M.A. (María A.); Pastor, M.A. (María A.); Larriva-Hormigos, M. (María); Prieto, J. (Jesús); Enriquez-de-Salamanca, R. (Rafael); Fontanellas-Romá, A. (Antonio); Morales-Urteaga, X. (Xabier); Cussó, L. (Lorena); Alegre-Esteban, M. (Manuel); Sampedro, A. (Ana); Jericó-Asenjo, D. (Daniel)The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyze brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice.
- Exploring current and emerging therapies for porphyrias(John Wiley & Sons, 2024) Deybach, J.C. (Jean-Charles); Anderson, K.E. (Karl E.); Avila, M.A. (Matías Antonio); Córdoba, K.M. (Karol M.); Urigo, F. (Francesco); Enriquez-de-Salamanca, R. (Rafael); Fontanellas-Romá, A. (Antonio); Jericó-Asenjo, D. (Daniel)Porphyrias are rare, mostly inherited disorders resulting from altered activity of specific enzymes in the haem synthesis pathway that lead to accumulation of pathway intermediates. Photocutaneous symptoms occur when excess amounts of photoreactive porphyrins circulate in the blood to the skin, whereas increases in potentially neurotoxic porphyrin precursors are associated with neurovisceral symptoms. Current therapies are suboptimal and their mechanisms are not well established. As described here, emerging therapies address underlying disease mechanisms by introducing a gene, RNA or other specific molecule with the potential to cure or slow progression of the disease. Recent progress in nanotechnology and nanoscience, particularly regarding particle design and formulation, is expanding disease targets. More secure and efficient drug delivery systems have extended our toolbox for transferring specific molecules, especially into hepatocytes, and led to proof-of-concept studies in animal models. Repurposing existing drugs as molecular chaperones or haem synthesis inhibitors is also promising. This review summarizes key examples of these emerging therapeutic approaches and their application for hepatic and erythropoietic porphyrias.
- Understanding carbohydrate metabolism and insulin resistance in acute intermittent porphyria(2023) Solares, I. (Isabel); Córdoba, K.M. (Karol M.); Ena, J. (Javier); Enriquez-de-Salamanca, R. (Rafael); Fontanellas-Romá, A. (Antonio); Morales-Conejo, M. (Monserrat); Jericó-Asenjo, D. (Daniel)Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking alpha-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP.
- Systemic messenger RNA as an etiological treatment for acute intermittent porphyria(2018) Berraondo, P. (Pedro); Kenney, M. (Matthew); Frassetto, A. (Andrea); Sathyajith-Kumarasinghe, E.; Martini, P. (Paolo); Lukacs, C. M. (Christine M.); Zhu, X. (Xuling); Butcher, W. (William); Avila, M.A. (Matías Antonio); Kalariya, M. (Mayur); Salerno, T. (Timothy); Guey, L. T. (Lin); Pejenaute-Martínez-de-Lizarrondo, Á. (Álvaro); Santamaría, E. (Eva); Fontanellas-Romá, A. (Antonio); Sabnis, S. (Staci); Burke, K. (Kristine); Alegre-Esteban, M. (Manuel); Sampedro, A. (Ana); Jericó-Asenjo, D. (Daniel); Park, J. (Ji-Sun); Benenato, K. E. (Kerry E.); Jiang, L. (Lei)Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP.
- The alpha-lipoic acid improves glucose metabolism and hyperinsulinemia in Acute Intermittent Porphyria: a nutritional concept for the management of rare disorders(2024) Paolini, E. (Erika); Di-Pierro, E. (Elena); Meroni, M. (Marica); Córdoba-Quiñones, K. M. (Karol Marcela); Dongiovanni, P. (Paola); Fontanellas-Romá, A. (Antonio); Longo, M. (Miriam); Battistin, M. (Michelle); Jericó-Asenjo, D. (Daniel); Gatti, S. (Stefano)
- Recombinant porphobilinogen deaminase targeted to the liver corrects enzymopenia in a mouse model of acute intermittent porphyria(2022) Berraondo, P. (Pedro); Corrales, F.J. (Fernando José); Martini, P. (Paolo); Lanciego, J.L. (José Luis); Córdoba-Quiñones, K. M. (Karol Marcela); Serrano-Mendioroz, I. (Irantzu); Prieto, J. (Jesús); Fontanellas-Romá, A. (Antonio); Merino-Díaz, M. (María); Garrido, M.J. (María Jesús); Alegre-Esteban, M. (Manuel); Sampedro, A. (Ana); Jericó-Asenjo, D. (Daniel); Jiang, L. (Lei)Correction of enzymatic deficits in hepatocytes by systemic administration of a recombinant protein is a desired therapeutic goal for hepatic enzymopenic disorders such as acute intermittent porphyria (AIP), an inherited porphobilinogen deaminase (PBGD) deficiency. Apolipoprotein A-I (ApoAI) is internalized into hepatocytes during the centripetal transport of cholesterol. Here, we generated a recombinant protein formed by linking ApoAI to the amino terminus of human PBGD (rhApoAI-PBGD) in an attempt to transfer PBGD into liver cells. In vivo experiments showed that, after intravenous injection, rhApoAI-PBGD circulates in blood incorporated into high-density lipoprotein (HDL), penetrates into hepatocytes, and crosses the blood-brain barrier, increasing PBGD activity in both the liver and brain. Consistently, the intravenous administration of rhApoAI-PBGD or the hyperfunctional rApoAI-PBGD-I129M/N340S (rApoAI-PBGDms) variant efficiently prevented and abrogated phenobarbital-induced acute attacks in a mouse model of AIP. One month after a single intravenous dose of rApoAI-PBGDms, the protein was still detectable in the liver, and hepatic PBGD activity remained increased above control values. A long-lasting therapeutic effect of rApoAI-PBGDms was observed after either intravenous or subcutaneous administration. These data describe a method to deliver PBGD to hepatocytes with resulting enhanced hepatic enzymatic activity and protection against AIP attacks in rodent models, suggesting that the approach might be an effective therapy for AIP.
- Management of hyponatremia associated with acute porphyria-proposal for the use of tolvaptan(AME, 2020) Solares, I. (Isabel); Tejedor, M. (Marta); Tejedor-Jorge, A. (Alberto); Enriquez-de-Salamanca, R. (Rafael); Fontanellas-Romá, A. (Antonio); Morales-Conejo, M. (Monserrat); Jericó-Asenjo, D. (Daniel)Hyponatremia is a common feature during the neurovisceral acute attacks which characterize hepatic porphyrias, as well as a sign of its severity. Therapeutic options for first-line acute attacks are intravenous administration of glucose and/or exogenous heme. The former treatment can aggravate hyponatremia by dilution and cause seizures; thus, the correction of hyponatremia must be carried out with extreme caution. This review summarizes recommendations for the management of hyponatremia during acute episodes of porphyria. Hyponatremia should be corrected slowly and seizures treated with medications in order to not exacerbate motor and sensory axonal neuropathy. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered a frequent cause of hyponatremia in acute porphyrias and must be identified as a symptom of an acute porphyria attack. Tolvaptan produces aquaresis and is considered a safe drug in porphyria. However, its use has only been reported in isolated cases during a porphyria attack. The convenience and usefulness of this drug in acute porphyria are discussed.