The Role of Next Generation Biologics in CV Disease

The multi-part session, “On Deck: Next Generation Biologics,” was part of a larger session at the Transcatheter Cardiovascular Therapeutics (TCT) conference, called “Strategies for Cardiovascular Repair: Stem Cells and Beyond.” The first portion on extracellular matrices and related products was presented by Karen Christman, PhD, associate professor of bioengineering at the University of California San Diego. Dr Christman discussed the use biomaterials for treating the extracellular matrix of the heart after MI. This matrix provides structural framework and important biochemical cues that can be used to direct repair and regeneration. She discussed 2 different methods of biomaterial delivery: an epicardial patch and an injectable material. By recreating the structural framework, endogenous cells will repopulate the area of infarct and help repair it. Dr Christman and colleagues developed a form of native cardiac extracellular matrix from porcine ventricles that can be delivered via catheter to the heart. Rodent studies have shown that after delivery, there is reassembly of the scaffold and recruitment of cells into the area for up to 3 weeks. They have also demonstrated that this results in improved global and regional cardiac function, decreased collagen (scar) formation, and increased myocardial matrix and endocardial muscle.

The second portion, called “Small Molecules and mi-RNAs,” was delivered by Stefanie Dimmeler, PhD, director of the Institute of Cardiovascular Regeneration at the University of Frankfurt in Germany. Dr Dimmeler began by explaining that microRNAs, roughly 22 nucleotides long, can result in mRNA degradation or translational repression. By modulating pathways, they can change expression of a network of genes, not just a single gene. microRNAs can also be used as biomarkers of disease. Several of them are known to control or enhance angiogenesis, cardiac reprogramming, and cardiomyocyte proliferation. In particular, miR-92a has been shown to block angiogenic sprouting in vitro and in model organisms. It is expressed in vessels and cardiomyocytes. Dr Dimmeler and team then studied the effects of antagomir-92a and LNA-92a, which block expression of miR-92a in animal hearts. It was shown that antagomir-92 improves myocardial recovery after ischemia. Additionally, local delivery of LNA-92a demonstrated inhibition of miR-92a expression in non-infarct as well as infarcted regions of the heart and reduced the infarct size. Local delivery was more effective than IV delivery in improvement of global function. It is thought that the mechanism is significant improvement in capillary density and decrease in cardiac muscle cell death. Inflammation was also significantly reduced in the infarcted tissue. In summary, the short-term inhibition of miR-92a improved the recovery of cardiac function after ischemia in mice and pigs.

“Induced Pluripotent Cells” was the final presentation of the session, given by Joseph C. Wu, MD, PhD, professor of medicine and director of the Stanford Cardiovascular Institute at Stanford School of Medicine. Dr Wu described 3 cardiac applications of induced pluripotent cells (iPSCs). The first is disease modeling; he gave examples of how iPSCs are helping us to understand the molecular mechanisms of hypertrophic and dilated cardiomyopathies. The second application is drug discovery and pharmacogenomics. The third is cell therapy, either autologous or allogeneic. He stated that this field is moving very quickly, and several human iPSC trials are currently planned. In fact, a group in Japan is now recruiting patients for a study to evaluate autologous iPSC injections in patients with macular degeneration.