Generx Biology & Delivery

Illustration by Brian Christie

Ad5FGF-4 Construct CAR Receptor
Binding for Localized Cardiac Transfection

FGF-4 – The Therapeutic Growth Factor

Generx is an adenovector (serotype 5) DNA-based gene therapy construct that encodes the Fibroblast Growth Factor-4 (FGF-4) gene. In transfected heart cells, using Cardium’s proprietary methods of gene therapy, Generx drives the cellular production of FGF-4, a secreted protein that activates other angiogenic growth factor pathways (such as VEGF, PDGF, HGF and nitric oxide), indicating that it is high in the hierarchical control of the angiogenic cascade. Company-sponsored research demonstrated that Generx has the capacity to promote and enhance cardiac microvascular circulation through both the enlargement of pre-existing collateral arterioles (arteriogenesis) and the formation of new capillary vessels (angiogenesis).

Taxus Cardium has developed a new and unique, in vitro angiogenesis bio-assay that provides a valuable tool for demonstrating the pro-angiogenic potency of Generx. This assay quantifies two key biological activities:

  • The dose-dependent release of the FGF-4 protein from Ad5FGF-4 transfected cells
  • The ability of the released FGF-4 in the “conditioned” transfected cell culture media to promote endothelial tube formation (angiogenesis) when added to a second co-culture containing human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts (HDF).

Generx-Biogenesis-Assay

Innovative Generx Intracoronary Delivery

Generx is designed to bind to cell surface Coxsackievirus-Adenovirus Receptors that are abundant in the heart and accessed using the Company’s proprietary ischemia-driven method of gene therapy. Lessons learned from the extensive preclinical and clinical experience with Generx include the finding that induction of transient ischemia during intracoronary Generx administration, together with the introduction of nitroglycerin, significantly facilitates the transfection of Generx into heart cells by several mechanisms, including enhanced penetration through microvessel endothelium and upregulation of Coxsackie-Adenovirus Receptor (CAR).[i]

Taxus Cardium has therefore developed an innovative proprietary method for Generx delivery which combines antegrade intracoronary artery delivery during transient balloon occlusion of a coronary artery, producing transient myocardial ischemia, and concomitant infusion of nitroglycerin, all of which can be safely applied by interventional cardiologists.

  • One-time treatment via a non-surgical delivery by intracoronary administration by interventional cardiologist during angiography procedure
  • Utilizes standard balloon catheter which can be easily integrated into diagnostic angiography procedures or with other percutaneous coronary interventions
  • New induced transient ischemia / reperfusion techniques designed to enhance DNA uptake and FGF-4 expression in the heart
  • 40% administered to right coronary circulation and 60% to left coronary circulation

[i] Shi et al., Hum Gene Ther Methods. 2012; 23(3):204-12.