title: Effects of neuregulin GGF2 (cimaglermin alfa) dose and treatment frequency on left ventricular function in rats following myocardial infarction.
abstract: Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1β isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro, GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7-14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans.
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Rd, Ardsley, NY 10502, USA. Electronic address: tparry@acorda.com.
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Parry
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Rd, Ardsley, NY 10502, USA. Electronic address: aganguly@acorda.com.
authors.forename: Anindita
authors.initials: A
authors.lastname: Ganguly
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Rd, Ardsley, NY 10502, USA. Electronic address: etroy@acorda.com.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Troy
authors.affiliation: Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA. Electronic address: jguerrero@partners.org.
authors.forename: J
authors.initials: J
authors.lastname: Luis Guerrero
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Rd, Ardsley, NY 10502, USA. Electronic address: jiaci@acorda.com.
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Iaci
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Rd, Ardsley, NY 10502, USA. Electronic address: msrinivas@acorda.com.
authors.forename: Maya
authors.initials: M
authors.lastname: Srinivas
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Rd, Ardsley, NY 10502, USA. Electronic address: avecchione@acorda.com.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Vecchione
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Rd, Ardsley, NY 10502, USA. Electronic address: dbutton@acorda.com.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Button
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Rd, Ardsley, NY 10502, USA. Electronic address: chackett@acorda.com.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Hackett
authors.affiliation: University of Nebraska Medical Center, 982265 S 42nd St & Emile St, Omaha, NE 68198, USA. Electronic address: ronald.zolty@unmc.edu.
authors.forename: Ronald
authors.initials: R
authors.lastname: Zolty
authors.affiliation: Maine Medical Center, 22 Bramhall St, Portland, ME 04102, USA. Electronic address: dsawyer@mmc.org.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
authors.affiliation: Acorda Therapeutics, Inc., 420 Saw Mill River Rd, Ardsley, NY 10502, USA. Electronic address: tcaggiano@acorda.com.
authors.forename: Anthony O
authors.initials: AO
authors.lastname: Caggiano
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019610:Cytoprotection / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects; D004334:Drug Administration Schedule; D006333:Heart Failure / Q000150:complications; D006352:Heart Ventricles / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology*; D020890:Neuregulin-1 / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D066247:Receptor, ErbB-4 / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000188:drug therapy*
chemical_list: C094131:NRG1 protein, human; D020890:Neuregulin-1; D004317:Doxorubicin; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4
keywords: Glial growth factor 2 (GGF2); Heart failure; Neuregulin; Rat