Centre de Référence Maladies Rares

U1035 INSERM

Biotherapy of genetic diseases, inflammatory disorders and cancers (BMGIC)

FR: Biologie Fondamentale Appliquée à la Médecine

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Biotherapy team
Project 1.1

iPSCs & hematopoïetic differentiation application to erythropoietic porphyrias

keywords: porphyrias, iPSC, stem cells, gene therapy

Description:

Our initial project focused on the congenital erythropoietic porphyrias (CEP) which are caused by genetic deficiencies of the biosynthetic pathway leading to deleterious porphyrin accumulation in bone marrow, red blood cells, spleen and liver causing organ impairment and cutaneous photosensitivity. Our goal was to implement an alternative to allogeneic bone marrow transplant to cure the most severe forms of CEP using lentiviral gene transfer and homologous recombination with CRISPR-Cas9 into autologous haematopoietic stem cells. The proof of concept of a successful gene therapy for this disease by transplantation of genetically modified HSCs was obtained, but recent reports of proviral insertional leukaemogenesis underscored the need for safer methods. Because of the rarity of candidate patients for CEP gene therapy and the genotoxicity risk, no clinical trial was started. The clonal approach allowed by induced pluripotent stem cells (iPSCs) could overcome the risk of insertional oncogenesis. We reported the feasibility of porphyria gene therapy with the use of iPSCs, with control of proviral integration site in a safe harbor. Although biosafety concerns need still to be addressed for clinical translation, regenerative therapy for CEP and other genetic red blood cell disorders is very promising. In addition, we have developed an alternative pharmacological approach with the use of proteasome inhibitors. Indeed, the C73R and the P248Q UROS mutations induce premature destruction of an otherwise catalytically active protein by proteasome in erythroid cells. In our CEP murine model, Bortezomib (Velcade) reduced porphyrin accumulation in circulating RBCs and urine, and reversed skin photosensitivity. These results of medical importance pave the way for pharmacologic treatment of CEP disease by preventing enzymatically active UROS mutants from early degradation by using proteasome inhibitors or chemical chaperones.

Related publications:

  • Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria. Urquiza P, Laín A, Sanz-Parra A, Moreno J, Bernardo-Seisdedos G, Dubus P, González E, Gutiérrez-de-Juan V, García S, Eraña H, San Juan I, Macías I, Ben Bdira F, Pluta P, Ortega G, Oyarzábal J, González-Muñiz R, Rodríguez-Cuesta J, Anguita J, Díez E, Blouin JM, de Verneuil H, Mato JM, Richard E, Falcón-Pérez JM, Castilla J, Millet O. Sci Transl Med. (2018-09-19) PMID: 30232228
  • Acquired erythropoietic uroporphyria and myelodysplastic syndrome cured by bone marrow transplantation. de Verneuil H Br J Dermatol. (2018-08) PMID: 30141566
  • Missense UROS mutations causing congenital erythropoietic porphyria reduce UROS homeostasis that can be rescued by proteasome inhibition. Blouin JM, Bernardo-Seisdedos G, Sasso E, Esteve J, Ged C, Lalanne M, Sanz-Parra A, Urquiza P, de Verneuil H, Millet O, Richard E. Hum Mol Genet. (2017-04-15) 26(8):1565-1576. doi: 10.1093
  • Preventing Pluripotent Cell Teratoma in Regenerative Medicine Applied to Hematology Disorders A Bedel, F Beliveau, I Lamrissi-Garcia, B Rousseau, I Moranvillier, B Rucheton, V Guyonnet-Duperat, B Cardinaud, H De Verneuil, F Moreau-Gaudry, S Dabernat. Stem cell Trans med (2016-09-07) 10.5966/sctm.2016-0201
  • Antisense oligonucleotide-based therapy in human erythropoietic protoporphyria. Oustric V, Manceau H, Ducamp S, Soaid R, Karim Z, Schmitt C, Mirmiran A, Peoc'h K, Grandchamp B, Beaumont C, Lyoumi S, Moreau-Gaudry F, Guyonnet-Dupérat V, de Verneuil H, Marie J, Puy H, Deybach JC, Gouya L. Am J Hum Genet. (2014-04-03) 94(4):611-7
  • Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria. Blouin JM, Duchartre Y, Costet P, Lalanne M, Ged C, Lain A, Millet O, de Verneuil H, Richard E. Proc Natl Acad Sci U S A (2013-11-05) doi: 10.1073/pnas.1314177110
  • HIF-2α Protects Human Hematopoietic Stem/ Progenitors and Acute Myeloid Leukemic Cells from Apoptosis Induced by Endoplasmic Reticulum Stress. Cell Rouault-Pierre K, Lopez-Onieva L, Foster K, Anjos-Afonso F, Lamrissi-Garcia I, Serrano-Sanchez M, Mitter R, Ivanovic Z, de Verneuil H, Gribben J, Taussig D, Rezvani HR, Mazurier F, Bonnet D. Stem Cell. (2013)
  • Metabolic Correction of Congenital Erythropoietic Porphyria using iPSCs free of Reprogramming Factors. Bedel A, Taillepierre M, Guyonnet-Duperat V, Lippert E, Dubus P, Dabernat S, Mautuit T, Cardinaud B, Pain C, Rousseau B, Lalanne M, Ged C, Duchartre Y, Richard E, de Verneuil H, Moreau-Gaudry F. Am J Hum Genet (2012) 89: 111-121
  • ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria. To-Figueras J, Ducamp S, Clayton J, Badenas C, Delaby C, Ged C, Lyoumi S, Gouya L, de Verneuil H, Beaumont C, Ferreira GC, Deybach JC, Herrero C, Puy H. Blood. (2011-08-11) 118(6):1443-51
  • Neonatal bone marrow transplantation prevents liver disease in a murine model of erythropoietic protoporphyria. Duchartre Y, Petit N, Moya C, Lalanne M, Dubus P, de Verneuil H, Moreau-Gaudry F, Richard E. J Hepatol. (2011-07) 55(1):162-170

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