Catheter-based gene therapy for HF
Wed, 07 Mar 2001 00:10:00
Durham, NC - A novel gene therapy - Adeno-betaARKct -, delivered by catheter to failing rabbit hearts, significantly restores ventricular function, according to a report in the March 6, 2001 issue of Circulation. This finding, if replicable in humans, could mean molecular ventricular assistance for heart failure (HF) patients awaiting heart transplant.
Human and animal failing hearts have in common a disruption of the beta-adrenergic receptor (beta-AR) signaling pathway. Namely, beta-AR is downregulated and desensitized in failing hearts. One of the critical factors mediating this disruption and the resulting myocardial dysfunction appears to be an increased presence of beta-AR kinase (beta-ARK1) in the heart. Beta-ARK1 acts on beta-AR to desensitize the receptor. This makes beta-ARK1 an attractive target for HF therapy. Previous animal studies have shown that inhibition of beta-ARK1, by genetic manipulation, can protect the heart against induction of heart failure.
In the present study, Dr Walter Koch (Duke University Medical School, Durham, NC) and colleagues demonstrate that inhibition of beta-ARK1, in animals in which HF has already been induced, can restore beta-AR responsiveness and reverse ventricular dysfunction.
Our model demonstrates that noninfarcted yet dysfunctional myocardium may be rescued at a molecular level. Thus beta-ARK inhibition may represent a novel form of molecular ventricular assistance.
Koch and colleagues took a beta-ARK1 inhibitor (beta-ARKct) transgene and placed it in an adenovirus vector. They then introduced the resulting construct (Adeno-beta-ARKct) into 7 HF rabbits. The researchers used a novel catheter-delivery approach via the left circumflex coronary artery (LCx), thus restricting the construct to the LV of the rabbit hearts. These rabbits, three weeks previously had undergone ligation of a large marginal branch of the LCx to induce HF, and were experiencing disruption of the beta-AR signaling pathway and LV dysfunction.
One week after "infection" with the vector construct, the 7 rabbits showed restored responsiveness of beta-AR in the LV, but not in the RV, suggesting that the gene therapy had been effective and successfully targeted within the heart. Physiologic assessment revealed LV systolic shortening was improved by nearly 100% (p<0.05) and LV contractility tended towards improvement. Peak systolic BP was significantly increased (p<0.05) at 1 week. Although there was no change in LV end-diastolic pressure or HR, in HF rabbits that did not receive the gene therapy these parameter worsened over the week.
Koch and colleagues conclude, "Our model demonstrates that noninfarcted yet dysfunctional myocardium may be rescued at a molecular level. Thus beta-ARK inhibition may represent a novel form of molecular ventricular assistance." The authors note that beta-ARK inhibition may offer a novel strategy for both gene therapy and pharmacotherapy.
In a Duke University press release, Koch predicts, "If our work continues to progress as it has, we anticipate being able to possibly test this approach in a certain group of patients within 3 years.... We would like to try it first on severe heart failure patients in the hospital awaiting a heart transplant to see if we could reverse the dysfunctioning part of the heart - sort of like a molecular assist device." Koch notes, the catheter-based delivery system shown to be effective in the current study will make gene therapy more feasible in these very sick patients who could not otherwise withstand a more invasive procedure.
Durham, NC - A novel gene therapy - Adeno-betaARKct -, delivered by catheter to failing rabbit hearts, significantly restores ventricular function, according to a report in the March 6, 2001 issue of Circulation. This finding, if replicable in humans, could mean molecular ventricular assistance for heart failure (HF) patients awaiting heart transplant.
Human and animal failing hearts have in common a disruption of the beta-adrenergic receptor (beta-AR) signaling pathway. Namely, beta-AR is downregulated and desensitized in failing hearts. One of the critical factors mediating this disruption and the resulting myocardial dysfunction appears to be an increased presence of beta-AR kinase (beta-ARK1) in the heart. Beta-ARK1 acts on beta-AR to desensitize the receptor. This makes beta-ARK1 an attractive target for HF therapy. Previous animal studies have shown that inhibition of beta-ARK1, by genetic manipulation, can protect the heart against induction of heart failure.
In the present study, Dr Walter Koch (Duke University Medical School, Durham, NC) and colleagues demonstrate that inhibition of beta-ARK1, in animals in which HF has already been induced, can restore beta-AR responsiveness and reverse ventricular dysfunction.
Our model demonstrates that noninfarcted yet dysfunctional myocardium may be rescued at a molecular level. Thus beta-ARK inhibition may represent a novel form of molecular ventricular assistance.
Koch and colleagues took a beta-ARK1 inhibitor (beta-ARKct) transgene and placed it in an adenovirus vector. They then introduced the resulting construct (Adeno-beta-ARKct) into 7 HF rabbits. The researchers used a novel catheter-delivery approach via the left circumflex coronary artery (LCx), thus restricting the construct to the LV of the rabbit hearts. These rabbits, three weeks previously had undergone ligation of a large marginal branch of the LCx to induce HF, and were experiencing disruption of the beta-AR signaling pathway and LV dysfunction.
One week after "infection" with the vector construct, the 7 rabbits showed restored responsiveness of beta-AR in the LV, but not in the RV, suggesting that the gene therapy had been effective and successfully targeted within the heart. Physiologic assessment revealed LV systolic shortening was improved by nearly 100% (p<0.05) and LV contractility tended towards improvement. Peak systolic BP was significantly increased (p<0.05) at 1 week. Although there was no change in LV end-diastolic pressure or HR, in HF rabbits that did not receive the gene therapy these parameter worsened over the week.
Koch and colleagues conclude, "Our model demonstrates that noninfarcted yet dysfunctional myocardium may be rescued at a molecular level. Thus beta-ARK inhibition may represent a novel form of molecular ventricular assistance." The authors note that beta-ARK inhibition may offer a novel strategy for both gene therapy and pharmacotherapy.
In a Duke University press release, Koch predicts, "If our work continues to progress as it has, we anticipate being able to possibly test this approach in a certain group of patients within 3 years.... We would like to try it first on severe heart failure patients in the hospital awaiting a heart transplant to see if we could reverse the dysfunctioning part of the heart - sort of like a molecular assist device." Koch notes, the catheter-based delivery system shown to be effective in the current study will make gene therapy more feasible in these very sick patients who could not otherwise withstand a more invasive procedure.
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