Researchers at Jefferson Medical College and Duke University have used gene therapy to help damaged heart cells regain strength and beat normally again in the laboratory. The work takes the scientists one step closer to eventual clinical trials in humans.
Walter Koch, Ph.D., director of the Center for Translational Medicine of the Department of Medicine at Jefferson Medical College of Thomas Jefferson University in Philadelphia, and his colleagues at Duke used a virus to carry a gene into the heart cells of individuals who had suffered from congestive heart failure. The gene introduced into these heart cells blocks the activity of an enzyme that is increased in failing human hearts and which contributes to the loss of the heart's contractile strength during the development of heart failure. When the activity of this enzyme is blocked by the gene therapy, the heart cells were able to contract at normal strength and their overall performance was improved.
Dr. Koch and his co-workers at Duke University Medical Center in Durham, N.C., report their findings April 6, 2004, in Circulation, a journal of the American Heart Association.
According to Dr. Koch, who is W.W. Smith Professor of Medicine at Jefferson Medical College of Thomas Jefferson University, researchers have known for some time that the beta-adrenergic receptor system fails to work properly in individuals with congestive heart failure. Such receptors "drive the heart ľ both by rate and force of contraction," he says.
The researchers' target has been the beta-adrenergic kinase (▀ARK1), an enzyme that is elevated in human heart failure. One of its functions is to turn off beta-adrenergic receptors. "In heart failure, beta adrenergic receptor density is decreased, ▀ARK is increased and both together cause dysfunctional beta receptor signaling," Dr. Koch says. "A failing heart then has little capacity to respond to exercise or stress because there are fewer receptors and the remaining receptors are more or less turned off.
"We have thought that inhibiting ▀ARK activity could increase signaling and increase function," he explains. In the laboratory dish, the researchers infected heart cells from patients who underwent cardiac transplantation due to end-stage heart failure with an adenovirus that encoded both ▀ARKct ľ a peptide that can block ▀ARK ľ and a so-called "reporter gene" protein, which glows green. The latter provided a signal to the scientists that the inhibitor was indeed present in the heart cells. They then were able to use a video camera to actually measure how strong the individual heart cells were beating. The virus used in this study is a version of the common cold virus that has been rendered non-infectious and serves to carry the therapeutic gene to the failing heart cells.
"We put the ▀ARKct into the cells, and failing human hearts become more like normal hearts, based on their ability to contract and other functional properties of these cells was also improved," Dr. Koch says. "This is the first work in actual human hearts to show efficacy of ▀ARKct as a potential therapy and more importantly, proves that the enzyme ▀ARK1 is a target for heart failure treatment."
"This study is the last proof of concept," he adds, noting that years of previous work in various animal models enabled the research team to reach this point. "Now we are dealing with human cells from failing human hearts," he says, noting that essentially these studies in human heart cells "confirm all we have done."
Congestive heart failure affects nearly 5 million Americans, many of whom have poor long-term prognoses, despite recent therapeutic advances. Dr. Koch hopes that such studies will move gene therapy forward as a viable option for heart failure patients. He notes that pre-clinical studies in "clinically relevant" large animal models are progressing, and should eventually lead to human trials using the ▀ARKct gene.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
Published on PsychCentral.com. All rights reserved.
Affirmations are like prescriptions for certain aspects of yourself you want to change.
-- Jerry Frankhauser