Today before the opening bell, Cardium Therapeutics announced the publication of preclinical findings demonstrating that cardiac ischemia is an important part of adenovector gene delivery (transfection) in mammalian hearts. The new findings were published in the peer-reviewed journal Human Gene Therapy Methods in an article titled “Ischemia-Reperfusion Increases Transfection Efficiency of Intracoronary Adenovirus type 5 in Pig Heart in Situ,” which is available online at http://online.liebertpub.com/doi/full/10.1089/hgtb.2012.048.
The published findings demonstrate Cardium’s innovative technique to employ transient cardiac ischemia to dramatically enhance gene delivery and transfection efficiency after one-time intracoronary administration of adenovector in mammalian hearts. Two consecutive but brief periods of coronary artery occlusion combined with co-administration of nitroglycerin increased both adenovector presence (measured by PCR) and transgene expression (assessed by luciferase activity) by over two orders of magnitude (>100 fold) in the heart, as compared to prior intracoronary artery delivery methods.
“The clinical success of DNA-based therapies can be enhanced by employing optimized gene delivery methods,” stated Dr. Gabor M. Rubanyi, Cardium’s Chief Scientific Officer and co-author of the published paper. “In addition, data analysis from the AGENT 1 through 4 clinical studies, involving more than 650 patients in Phase 1/2 through Phase 2/3, showed that patients with more severe forms of coronary artery disease – which is associated with increased ischemia – tended to be more responsive to the one-time administration of Generx than patients with less severe disease. The research results published in Human Gene Therapy Methods extend those findings and demonstrate that Cardium’s new technique for adenovector gene delivery in the heart can be used to dramatically boost adenovector delivery. By enhancing uptake even in patients with less severe forms of disease and ischemia, it would be expected to reduce response variability and allow for the potential treatment of patients with a broader range of associated coronary artery disease. The new treatment protocols for Cardium’s recently-initiated ASPIRE clinical study have been developed to use our knowledge about induced transient ischemia techniques to leverage these research findings and enhance the non-surgical, catheter-based delivery of Generx to the heart.”
The company’s new technique of adenovector delivery to the heart benefits from the fact that transient ischemia may reduce the permeability barrier of the vascular endothelium and may increase the number of available coxsackie-adenovirus receptors mediating adenovector uptake. Balloon angioplasty catheters have been used for many years to expand blocked coronary arteries, sometimes with use of a stent, and these catheters have also been used safely by cardiologists in patients with coronary artery disease to study the effects of brief ischemia. Cardium’s new method inflates the balloon in non-narrowed coronary artery areas to only briefly interrupt flow using inflation pressure that is significantly less than that used for performing routine angioplasty procedures.
Cardium’s recently initiated Russian-based ASPIRE Phase 3 registration study of patients with chronic myocardial ischemia and advanced angina pectoris uses transient ischemia techniques during non-surgical percutaneous catheterization with a standard angioplasty catheter and the intracoronary infusion of nitroglycerin with the Generx® [Ad5FGF-4] product candidate. The company’s Generx product candidate is intended to stimulate the growth of collateral blood vessels to effectively bypass coronary artery atherosclerotic blockages without surgical procedures or angioplasty and stents.
As confirmed by today’s release, the studies published in Human Gene Therapy Methods were conducted at Emory University School of Medicine by Jakob Vinten-Johansen, Ph.D. and colleagues, and were co-sponsored by a Small Business Innovation Research grant from the National Institutes of Health (Cardium Therapeutics) and the Carlyle Fraser Heart Center (Emory). A presentation titled: “New Perspectives for Angiogenic Gene Therapy to Treat Myocardial Ischemia in Patients with Coronary Disease” was presented at the 2012 American Society of Gene & Cell Therapy Meeting in May 2012 and is available for viewing at http://www.cardiumthx.com/pdf/Generx-ASGCT-May-2012-Rubanyi.pdf. At the conference, Cardium also presented a late-breaking poster titled “Transient Ischemia is Necessary for Efficient Adenovector Gene Transfer in the Heart”. The poster presentation can be viewed at http://www.cardiumthx.com/pdf/Generx-ASGCT-Poster-Presentation-May-2012.pdf.
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