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analysis

+ Treatment effect, — No treatment effect

I.m. = Intramyocardial, I.e. = Intracoronary, I.v. = Intravenous.

SPECT - Single Photon Emission Computerized Tomography in neutralizing antibodies to the adenovirus. There was no significant improvement in primary end-point exercise capacity, neither for the individual doses nor for the polled data. In a subgroup analyse, an improvement was discovered in patients with baseline exercise time < 10min.

In the following double-blind placebo-controlled study AGENT-2 [25] they authors used 1010 ad5-FGF4 virus particle unit (pu)/patient and demonstrated improved myocardial perfusion compared to the placebo group. Based on these encouraging results they initiated the two larger multi-centre studies AGENT-3 and-4, aiming to include a total of 456 and 250 patients, respectively. However, these two trials were both stopped January 2004 after an interim analysis demonstrating insufficient evidence of efficacy. Hopefully, the results, from these two studier, will be published to increase the knowledge about efficacy and side-effects for the planning of future clinical gene therapy trials.

2.2.2. Trials with direct intramyocardial delivery of vascular growth factor genes

The majority of clinical VEGF gene therapy trials have used directly intramy-ocardial injection of the gene either during coronary by-pass surgery or by using a percutaneous delivery method [26]. The studies included patients with chronic stable angina due to angiographically documented coronary artery disease, which could not be treated with conventional therapy.

In an open study, Symes et al [27] (Table 3) injected via a mini-thoracotomy two different doses of plasmid VEGF-A165 (125 microgram (n = 10) and 250 microgram (n = 10)) intramyocardially into the antero-lateral region of the left ventricle with the patients in general anaesthesia without any problems. No side-effects were registered. Nuclear myocardial perfusion scans demonstrated an improvement 60 days after treatment. Using identical surgical set-up for gene transfer, Sylven et al [28,29] treated 6 patients with intramyocardial injections of 250 micrograms plasmid VEGF-A165. An improvement was registered in echocardiographic myocardial tissue Doppler velocity and in clinical status. Myocardial perfusion improved on SPECT in 3 of the 6 patients. One patient had a perioperative myocardial infarction. The results from 12 months follow-up in these patients demonstrated persistent improvement in clinical status and in echocardiography evaluation [29]. No long-term side-effects to the gene therapy was reported.

The invasive thoracotomy approach was also used in two trials testing the safety and efficacy of adenovirus transfection with the VEGF121 gene [30, 31] (Table 3). In the first study AdGVVEGF121 was injected intramyocardial in an area with reversible ischemia either as an adjunct to conventional CABG (n = 15) or as a sole therapy via a minithoracotomy (n = 6) [30]. Five different vector doses were used in the first patient group (4 x 109-4 x 1010 particle unit (pu)/patient), while the second group was treated with 4 x 109 pu/patient. No evidence of systemic or cardiac related adverse effects was reported, and no adenovirus was detected in peripheral blood samples. Only a slight increase

Table 3. Direct intramyocardial delivery of genes encoding for vascular growth factors for myocardial angiogenesis in chronic ischemic heart disease

Growth factors - Gene

Table 3. Direct intramyocardial delivery of genes encoding for vascular growth factors for myocardial angiogenesis in chronic ischemic heart disease

Growth factors - Gene

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