Treating Disease at the Genetic Level

Editor’s Corner | Alfred A. Bove, MD, PhD Editor-in-Chief, CardioSource WorldNews

In 1953, we learned that all of the structures in our bodies, and in all other living organisms, are built from coded information contained in the cell nucleus. Following the x-ray diffraction studies of Rosalind Franklin, the discovery by Watson and Crick of the double helix of deoxyribonucleic acid (DNA) —and the means by which the sequence of nucleic acids coded to build proteins that in turn built tissue and organ structures—was a landmark discovery that altered our understanding of biology. Since then, we have learned how the DNA information is transferred to an intermediate information system embodied in ribonucleic acid (RNA) and how RNA codes for the manufacture of proteins that, when fully assembled, create the living organism.

We quickly learned that DNA was bundled into groups called genes that held collections of specific functions; furthermore, there were a fixed number of genes in living species, there were differences in some genes that defined female and male, and various characteristics of a given person or animal were related to specific variations in the genetic structure. Genes reside in the chromosomes, and we humans have 46 of them.

So many important discoveries have been made regarding how the system functions that it is difficult to list them all, but inevitable questions come to mind. For example, how does the genetic structure relate to the many inherited disorders that have been observed over the history of clinical medicine? Many of the syndromes that we now characterize as defects in a specific gene structure were identified as genetic disorders without an understanding of how these genetic disorders evolved and where the abnormality that caused the disorder was located.

We can now trace congenital abnormalities to specific enzymes and have developed methods to alter the outcome via therapies designed to counter the metabolic defect. Such therapies have resulted in normal development in many children who had metabolic defects that otherwise would have caused life-long disabilities. Our understanding now encompasses the chromosomal variants that cause congenital syndromes such as Down’s and Turner’s syndromes, and we are identifying specific genetic changes that relate to various forms of cardiomyopathy, channelopathies, receptor sensitivities to medications, and metabolism of drugs. What’s more, we have discovered that genes can be modified by environmental factors, and often are altered by stress caused by various disease states.

These discoveries led to the new concept of epigenetics wherein gene action could be modified by environmental factors affecting the cell. Heart failure is an example of epigenetic changes induced by the heart failure condition. Attempts at modifying genetic structure have generally been unsuccessful and, in a few cases, have resulted in catastrophic results with demise of the subject. A logical advance would be to create genetic changes that would counter cellular changes related to various disease states.

The current interest is in heart failure caused by ischemic and nonischemic cardiomyopathies. Alterations in microvascular structure could be done by modifying genes that result in angiogenesis and intracellular metabolism of calcium in the failing myocyte could be affected by enhancing calcium transport in the myocyte. Identifying specificproteins that would enhance cellular function has been accomplished; the next step: induce the cell to produce intracellular mechanisms that improve myocyte function.

Either directly or by intracoronary infusion, we have tried to inject stem cells into the myocardium with marginal results. The assumption that the progenitor cells would either proliferate in the myocardium or, through cell signaling, induce existing myocytes to replicate has not demonstrated significant improvements in function in failing hearts. So we come to 2016 wherein attempts to modify the intracellular milieu by genetic manipulation unfolds as the next frontier in heart failure therapy.

With the understanding of the intracellular defects that accompany heart failure, we now see the possibility unfolding to alter specific intracellular mechanisms at the protein level using well-developed methods for inserting specific functional genes into the cell nucleus. These techniques and innovations allow the cell to produce new proteins that can improve cellular function and ameliorate heart failure.

While our medications to improve heart failure outcome have been successful, they don’t get to the heart of the problem: loss of myocytes. As you will read in this month’s cover story, this new approach, aimed at improving contractile function directly, is the future—but we still have a long way to go.

Alfred A. Bove, MD, PhD, is professor emeritus of medicine at Temple University School of Medicine in Philadelphia, and former president of the ACC.

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