Martini, P. (Paolo)
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- Disease pharmacokinetic–pharmacodynamic modelling in acute intermittent porphyria to support the development of mRNA-based therapies(2020) Parra-Guillen, Z.P. (Zinnia Patricia); Martini, P. (Paolo); Guey, L. T. (Lin); Hard, M. (Marjie); Fernández-de-Trocóniz, J.I. (José Ignacio); Fontanellas-Romá, A. (Antonio); Vera-Yunca, D. (Diego); Jericó-Asenjo, D. (Daniel); Jiang, L. (Lei)Background and Purpose Acute intermittent porphyria (AIP) results from haplo-insufficiency of the porphobilinogen deaminase (PBGD) gene encoding the third enzyme in the haem biosynthesis pathway. As liver is the main organ of pathology for AIP, emerging therapies that restore enzyme hepatic levels are appealing. The objective of this work was to develop a mechanistic-based computational framework to describe the effects of novel PBGD mRNA therapy on the accumulation of neurotoxic haem precursors in small and large animal models. Experimental Approach Liver PBGD activity data and/or 24-hr urinary haem precursors were obtained from genetic AIP mice and wild-type mice, rats, rabbits, and macaques. To mimic acute attacks, porphyrogenic drugs were administered over one or multiple challenges, and animals were used as controls or treated with different PBGD mRNA products. Available experimental data were sequentially used to build and validate a semi-mechanistic mathematical model using non-linear mixed-effects approach. Key Results The developed framework accounts for the different biological processes involved (i.e., mRNA sequence, release from lipid nanoparticle and degradation, mRNA translation, increased PBGD activity in liver, and haem precursor metabolism) in a simplified mechanistic fashion. The model, validated using external data, shows robustness in the extrapolation of PBGD activity data in rat, rabbit, and non-human primate species. Conclusion and Implications This quantitative framework provides a valuable tool to compare PBGD mRNA drug products during early preclinical stages, optimize the amount of experimental data required, and project results to humans, thus supporting drug development and clinical dose and dosing regimen selection.
- 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.
- 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.
- Messenger RNA therapy for rare genetic metabolic diseases(2019) Berraondo, P. (Pedro); Martini, P. (Paolo); Avila, M.A. (Matías Antonio); Fontanellas-Romá, A. (Antonio)Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called ‘protein replacement therapy’ could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.
- 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.