Japanese Circulation Society
Scientific Sessions Activities Publications
index
>congress report>the64th scientific session>special lecture
IS029

Gene Therapy for Cardiovascular Disease
Todd K. Rosengart, M.D.
Division of Cardiothoracic Surgery
Evanston Northwestern Healthcare
Evanston, IL, USA
 
  • Survey of trials
  • Adenovirus-mediated myocardial gene transfer

  • Gene therapy is one technology used in the strategy of therapeutic angiogenesis, a novel intervention in which specific mediators induce new blood vessel formation to revascularize ischemic tissues. For the foreseeable future, angiogenesis is most suitable to those patients with diffuse disease.

    The concept of therapeutic angiogenesis is guided by the complex biology of angiogenesis, and how it occurs is just beginning to be understood, as illustrated by endothelial cell function. A number of events must occur to induce angiogenesis. Fortunately, the addition of one of several angiogenic mediators is capable of inducing higher angiogenic responses.

    The observation in the ischemic porcine model that the vascular endothelial growth factor adenovirus AdGVVEGF121.10 induces a robust angiogenic response, collateralizes the ameroid restrictor and completely revascularizes the ischemic circumflex territory, and results from other investigators, has progressed the field of clinical therapeutic angiogenesis over the last few years.

    PAGE TOP

     


    Survey of trials


    A number of Phase I trials have looked at different mediators and delivery systems in myocardial therapeutic angiogenesis, essentially bypassing obstructive coronary artery disease (CAD). Several trials have shows that VEGF121 and VEGF165 and fibroblast growth factor (FGF) are angiogenic mediators. Mediators have been delivered in protein solution or via microcapsules or in a gene therapy form (plasmid, adenovirus). The two routes of delivery have been intracoronary/intravenous or intramyocardial (epicardial).

    Schumacher showed angiographic improvement at 3 months in patients who received fibroblast growth factor-1 (FGF-1). In this placebo-controlled, randomized, adjunct to coronary artery bypass trial, FGF-1 or inactivated FGF was injected into the territory of the LAD (20 patients per group). At 3 months, gray-scale analysis of angiography showed the FGF-1 patients had a higher lateral score compared to the control patients (59 vs 20, respectively).

    A Phase I study of intracoronary recombinant human VEGF (rhVEGF165), by Henry consisted of two studies. In Study I, the dose escalation study, two 10-minute intracoronary infusions were delivered. In Study II a 20-minute intracoronary infusion, supplemented by three 4-hr intravenous infusions on days 3, 6 and 9 were delivered. In Study I, on SPECT analysis 7 of the 15 patients (47%) showed improvement, and on angiogram 5 of 7 (71%) showed improvement. However, in the Phase II study, no clinical benefit was seen as evidenced by no improvement in either angina class or exercise tolerance test.

    In a study by Losordo in 16 patients, plasmid VEGF165 (125 mcg) was delivered into the anterolateral left ventricle via mini-thoracotomy by direct intramyocardial injection (4 injections, each 2 ml). In 66% of patients, there was complete resolution of angina. Weekly anginal episodes were reduced from 50.1 to 3 and weekly nitroglycerin use reduced from 60.7 to 2.5. Improvement in the ischemic territory was shown by dobutamine SPECT estimated scans and other analyses. Normally perfused segments increased from 6.9 to 8.9, and irreversibly ischemic segments reduced from 2.4 to 1.2. The stress perfusion ischemia score was reduced from 21 to 16.8 and the real perfusion ischemia score from 18.3 to 12.4.

    Laham used basic FGF (FGF-3) in a randomized, double blind, placebo-controlled trial as an adjunct to bypass surgery. Heparin alginate microcapsules carrying FGF-2 (10 mcg and 100 mcg doses) were delivered to the non-revascularized territory. At 3 months, the incidence of recurrent angina was significantly decreased to zero in the 100 mcg FGF-3 group (n=3, to 13% in the 10 mcg FGF-3 group (n=3), and 39% in the control group.

    Commentary

    FGF appears to be a potent angiogenic, however there is at least a theoretical risk of potential promiscuity as it can also induce smooth muscle cell hyperplasia and fibrosis.

    VEGF has multiple isoforms (206, 189, 165, 121) but it is presently unclear whether any will have a superior therapeutic effect. VEGF has an advantage due to its high specificity, theoretically minimizing the concern of smooth muscle cell hyperplasia and fibrosis.

    The intramyocardial route was a more efficient delivery route than the intracoronary route and significantly more efficient that the intravenous route to deliver high levels of VEGF expression localized to the heart, versus systemic effects. The epicardial route was more efficacious than the endocardial route in these early studies.

    Protein versus gene therapy-based strategies is an area of great debate. Gene therapy represents an alternative delivery system. However, the adenovirus is interesting because 1) it has high levels of expression, 2) it mediates expression in 1-2 weeks, which appears to be ideal for inducing angiogenesis, 3) direct administration to an organ yields local expression only, and 4) similar vectors have been safely used in humans.

    PAGE TOP

     


    Adenovirus-mediated myocardial gene transfer


    AdGVVEGF121.10 was used in two studies by Rosengart and colleagues. In the adjunct to bypass study, 15 patients were randomized to one of 5 dosage groups, ranging from 4x105 to 4x1010 particle units (3/group), with 1 coronary distribution per patient. At 2 years there were four deaths; one due to perioperative MI and one due to acute mesenteric embolus.

    In a gene-therapy-only minimally invasive surgery study conducted six months later, 16 patients were randomized to one of three dosage groups. Six were randomized to 4x109 particle units with 1 coronary distribution, 5 to 4x1010 particle units with 2 coronary distributions, and 5 to 4x1010 with 3 coronary distributions. These patients appeared to demonstrate symptomatic improvement at 6-month followup.

    No correlation was found for a variety of risk factors, including vector or transgene delivery. One specific parameter of interest was the anti-Ad-5 neutralizing antibodies; because of concerns regarding re-dosing preliminary data suggest this will be possible. In this Phase I study with a small number of patients and no placebo control, most of the patients with class 4 angina at baseline improved to class 1 by 1 month. Nitroglycerin use was reduced in most patients from about 15-27 per week to 8 or less by one month. Both effects persisted to 6 months.

    PAGE TOP

     


    Report Index | Previous Report | Next Report
    Scientific Sessions | Activities | Publications
    Index

    Copyright © 2000 Japanese Circulation Society
    All Rights Reserved.

    webmaster@j-circ.or.jp