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Yaniz-Galende E.,Mount Sinai School of Medicine | Chen J.,Mount Sinai School of Medicine | Chemaly E.,Mount Sinai School of Medicine | Liang L.,Mount Sinai School of Medicine | And 6 more authors.
Circulation Research | Year: 2012

RATIONALE: There is growing evidence that the myocardium responds to injury by recruiting c-kit cardiac progenitor cells to the damage tissue. Even though the ability of exogenously introducing c-kit cells to injured myocardium has been established, the capability of recruiting these cells through modulation of local signaling pathways by gene transfer has not been tested. OBJECTIVE: To determine whether stem cell factor gene transfer mediates cardiac regeneration in a rat myocardial infarction model, through survival and recruitment of c-kit progenitors and cell-cycle activation in cardiomyocytes, and explore the mechanisms involved. METHODS AND RESULTS: Infarct size, cardiac function, cardiac progenitor cells recruitment, fibrosis, and cardiomyocyte cell-cycle activation were measured at different time points in controls (n=10) and upon stem cell factor gene transfer (n=13) after myocardial infarction. We found a regenerative response because of stem cell factor overexpression characterized by an enhancement in cardiac hemodynamic function: an improvement in survival; a reduction in fibrosis, infarct size and apoptosis; an increase in cardiac c-kit progenitor cells recruitment to the injured area; an increase in cardiomyocyte cell-cycle activation; and Wnt/β-catenin pathway induction. CONCLUSIONS: Stem cell factor gene transfer induces c-kit stem/progenitor cell expansion in situ and cardiomyocyte proliferation, which may represent a new therapeutic strategy to reverse adverse remodeling after myocardial infarction. © 2012 American Heart Association, Inc. Source


The present invention relates to improved therapies for the treatment of heart disease, particularly the improved delivery of therapeutic agents to heart tissue by direct infusion into the coronary circulation. A preferred embodiment of the invention is a method comprising, identifying a mammal in need of treatment or prevention of heart disease, and supplying NO to the coronary circulation prior to, and/or during the infusion of a therapeutic polynucleotide into a blood vessel of the coronary circulation in vivo.


The present invention relates to improved therapies for the treatment of heart disease, particularly the improved delivery of therapeutic agents to heart tissue by direct infusion into the coronary circulation. A preferred embodiment of the invention is a method of treating or preventing a cardiovascular disease by transfecting cardiac cells of a large mammal, the method comprising, identifying a mammal in need of treatment or prevention of heart disease, supplying NO to the coronary circulation prior to, and/or during the infusion of a therapeutic polynucleotide into a blood vessel of the coronary circulation in vivo, where the therapeutic polynucleotide is infused into the blood vessel over a period of at least about three minutes, where the coronary circulation is not isolated or substantially isolated from the systemic circulation of the mammal; and where the therapeutic polynucleotide transfects cardiac cells of the animal resulting in the treatment or prevention of the heart disease.


LOS ANGELES--(BUSINESS WIRE)--Glancy Prongay & Murray LLP (“GPM”) announces the filing of a class action lawsuit on behalf of investors of Celladon Corporation (“Celladon” or the “Company”) (NASDAQ:CLDN), who purchased shares between July 7, 2014 and June 25, 2015, inclusive (the “Class Period”). Celladon investors have until August 31, 2015 to file a motion to serve as lead plaintiff in the class action. Celladon is a clinical-stage biotechnology company which is focused on the development of cardiovascular gene therapy and calcium dysregulation. The Company’s lead candidate is MYDICAR to treat inadequate pumping in heart failure patients. The complaint alleges that the Company potentially misled investors regarding the design of its MYDICAR clinical trials; and otherwise misled investors regarding the successful FDA approval of MYDICAR. On April 26, 2015, Celladon issued a press release announcing that the Company’s Phase 2b CUPID2 trial of MYDICAR did not meet its primary and secondary goals. As a result of this news, the price of Celladon stock plummeted $11.04 per share to close at $2.64 per share on April 27, 2015, a decline of 80% on volume of 32 million shares. On June 1, 2015, Celladon issued a press release announcing the abrupt resignation of defendant Krisztina M. Zsebo (“Zsebo”) as Chief Executive Officer (“CEO”) and a director. Then, on June 26, 2015, before the market opened, Celladon issued a press release announcing the suspension of its plans for further research or development of its MYDICAR program and other pre-clinical programs, and indicating the possibility that the Company could be liquidated with net cash available to shareholders of $25-$30 million. As a result of this news, the price of Celladon stock dropped $0.85 per share to close at $1.35 per share on June 26, 2015, a decline of 38% on volume of 9 million shares If you purchased shares of Celladon during the Class Period, have information or would like to learn more about these claims, or have any questions concerning this announcement or your rights or interests with respect to these matters, please contact Casey Sadler, of GPM, 1925 Century Park East, Suite 2100, Los Angeles, California 90067 at 310-201-9150, Toll-Free at 888-773-9224, by email to shareholders@glancylaw.com, or visit our website at http://www.glancylaw.com. If you inquire by email please include your mailing address, telephone number and number of shares purchased. This press release may be considered Attorney Advertising in some jurisdictions under the applicable law and ethical rules.


Zsebo K.,Celladon | Yaroshinsky A.,AY Statistical Consulting | Rudy J.J.,Celladon | Wagner K.,Celladon | And 3 more authors.
Circulation Research | Year: 2014

Rationale: The Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID 1) study was a phase 1/phase 2 first-in-human clinical gene therapy trial using an adeno-associated virus serotype 1 (AAV1) vector carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a) in patients with advanced heart failure. The study explored potential benefits of the therapy at 12 months, and results were previously reported. Objective: To report long-term (3-year) clinical effects and transgene expression in the patients in CUPID 1. Methods and results: A total of 39 patients with advanced heart failure who were on stable, optimal heart failure therapy were randomized to receive intracoronary infusion of AAV1/SERCA2a in 1 of 3 doses (low-dose, 6×1011 DNase-resistant particles; mid-dose, 3×10 12 DNase-resistant particles; and high-dose, 1×1013 DNase-resistant particles) versus placebo. The following recurrent cardiovascular and terminal events were tracked for 3 years in all groups: myocardial infarction, worsening heart failure, heart failure-related hospitalization, ventricular assist device placement, cardiac transplantation, and death. The number of cardiovascular events, including death, was highest in the placebo group, high but delayed in the low-and mid-dose groups, and lowest in the high-dose group. Evidence of long-term transgene presence was also observed in high-dose patients. The risk of prespecified recurrent cardiovascular events was reduced by 82% in the high-dose versus placebo group (P=0.048). No safety concerns were noted during the 3-year follow-up. Conclusions: After a single intracoronary infusion of AAV1/SERCA2a in patients with advanced heart failure, positive signals of cardiovascular events persist for years. © 2013 American Heart Association, Inc. Source

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