Derivatives of Erythropoietin That Are Tissue Protective But Not Erythropoietic

American Association for the Advancement of Science (AAAS) - Tập 305 Số 5681 - Trang 239-242 - 2004
Marcel Leist1,2,3,4,5, Pietro Ghezzi1,3,4,5, Giovanni Grasso1,3,4,5, Roberto Bianchi1,2,3,4,5, Pia Villa1,2,3,4,5, Maddalena Fratelli1,2,3,4,5, Costanza Savino1,2,3,4,5, Marina Bianchi1,2,3,4,5, Jacob Nielsen1,2,3,4,5, Jens Gerwien1,2,3,4,5, Pekka Kallunki1,2,3,4,5, Anna Kirstine Larsen1,2,3,4,5, Lone Helboe1,2,3,4,5, Søren Christensen1,2,3,4,5, Lars Østergaard Pedersen1,2,3,4,5, Mette Nielsen1,2,3,4,5, Lars Torup1,2,3,4,5, Thomas N. Sager1,2,3,4,5, Alessandra Sfacteria1,3,4,5, Serhat Erbayraktar1,6,3,4, Zübeyde Erbayraktar1,6,3,4, Necati Gökmen1,6,2,3,4, Osman Yılmaz1,6,3,4, A Cerami1,3,4,5, Q W Xie1,3,4,5, Thomas R. Coleman1,3,4,5, Bruce Beutler1,3,4,5, Michael Brines1,3,4,5
1Consiglio Nazionale delle Ricerche, Institute of Neuroscience, 20129 Milano, Italy.
2H. Lundbeck A/S, 2500 Valby, Denmark.
3“Mario Negri” Institute of Pharmacological Research, 20157 Milano, Italy
4The Kenneth S. Warren Institute, Ossining, NY 10562, USA.
5University of Messina, 98122, Messina, Italy
6Dokuz Eylul University School of Medicine, Izmir 35340, Turkey.

Tóm tắt

Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype–selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO.

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This work would not have been possible without substantial and excellent technical assistance which is gratefully acknowledged. This work is partially supported by grant RBAU01AR5J and by Fondo Integrativo Speciale per la Ricerca-Neurobiotecnologie from the Ministero dell'Istruzione Università e Ricerca Rome Italy (to P.G.). Cerami-Hand Cerami and Brines are officers and minority stockholders of Warren Pharmaceuticals. The following patents have been applied for concerning this work: PCT/US03/20964 PCT/US01/49479 and US 10/188 905.

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American Association for the Advancement of Science (AAAS)

Tập 305 Số 5681

239-242

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