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mRNA-based therapy in a rabbit model of variegate porphyria offers new insights into the pathogenesis of acute attacks.
Jericó, Daniel; Córdoba, Karol M; Jiang, Lei; Schmitt, Caroline; Morán, María; Sampedro, Ana; Alegre, Manuel; Collantes, María; Santamaría, Eva; Alegre, Estíbaliz; Culerier, Corinne; de Mendoza, Ander Estella-Hermoso; Oyarzabal, Julen; Martín, Miguel A; Peñuelas, Iván; Ávila, Matías A; Gouya, Laurent; Martini, Paolo G V; Fontanellas, Antonio.
Afiliação
  • Jericó D; Hepatology Program, Centre for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
  • Córdoba KM; Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
  • Jiang L; Hepatology Program, Centre for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
  • Schmitt C; Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
  • Morán M; Moderna Inc., Cambridge, MA 02139, USA.
  • Sampedro A; Centre de Recherche sur l'Inflammation, Institut National de la Santé et de la Recherche Médicale U1149, 75018 Paris, France.
  • Alegre M; Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes et Université de Paris, 92701 Colombes, France.
  • Collantes M; Mitochondrial Diseases Laboratory, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.
  • Santamaría E; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, Instituto de Salud Carlos III, 28029 Madrid, Spain.
  • Alegre E; Hepatology Program, Centre for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
  • Culerier C; Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
  • de Mendoza AE; Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
  • Oyarzabal J; Department of Clinical Neurophysiology, Clínica Universidad de Navarra (CUN), 31008 Pamplona, Spain.
  • Martín MA; Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
  • Peñuelas I; MicroPET Research Unit, CIMA-CUN, 31008 Pamplona, Spain.
  • Ávila MA; Nuclear Medicine Department, CUN, 31008 Pamplona, Spain.
  • Gouya L; Hepatology Program, Centre for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
  • Martini PGV; Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
  • Fontanellas A; Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
Mol Ther Nucleic Acids ; 25: 207-219, 2021 Sep 03.
Article em En | MEDLINE | ID: mdl-34458006
ABSTRACT
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.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2021 Tipo de documento: Article