Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

Leikas, Aleksi J.; Hassinen, Iiro; Hedman, Antti; Kivelä, Antti; Ylä‐Herttuala, Seppo; Hartikainen, Juha

doi:10.1038/s41434-021-00295-1

Cited by 19 publications

(14 citation statements)

References 22 publications

(26 reference statements)

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“…In conclusion, AdVEGF-D ΔNΔC is a promising new therapeutic candidate for severe coronary heart disease, as it induced angiogenesis, increased perfusion and improved cardiac function as well as increased the growth of functional lymphatic network. AdVEGF-D ΔNΔC has also entered clinical testing (Hartikainen et al, 2017;Korpela et al, 2021;Leikas et al, 2022). However further studies are needed to optimize the beneficial effects, evaluate the long-term safety and find the patient groups that may benefit from the treatment.…”

Section: Discussionmentioning

confidence: 99%

Adenoviral VEGF-DΔN ΔC gene therapy for myocardial ischemia

Pajula

Lähteenvuo

et al. 2022

Front. Bioeng. Biotechnol.

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Background: Cardiovascular diseases are the leading cause of death globally. In spite of the availability of improved treatments, there is still a large group of chronic ischemia patients who suffer from significant symptoms and disability. Thus, there is a clear need to develop new treatment strategies for these patients. Therapeutic angiogenesis is a novel therapy method which has shown promising results in preclinical studies. In this study, we evaluated safety and efficacy of adenoviral (Ad) VEGF-DΔNΔC gene transfer for the treatment of myocardial ischemia in a pig model.Methods: Adenoviral VEGF-DΔNΔC gene transfer was given to pigs (n = 26) via intramyocardial injections using an electromechanical injection catheter. Angiogenic effects were evaluated in an acute myocardial infarction model (n = 18) and functionality of the lymphatic vessels were tested in healthy porcine myocardium (n = 8). AdLacZ was used as a control.Results: AdVEGF-DΔNΔC induced safe and effective myocardial angiogenesis by inducing a four-fold increase in mean capillary area at the edge of the myocardial infarct six days after the gene transfer relative to the control AdLacZ group. The effect was sustained over 21 days after the gene transfer, and there were no signs of vessels regression. AdVEGF-DΔNΔC also increased perfusion 3.4-fold near the infarct border zone relative to the control as measured by fluorescent microspheres. Ejection fraction was 8.7% higher in the AdVEGF-DΔNΔC treated group 21 days after the gene transfer relative to the AdLacZ control group. Modified Miles assay detected a transient increase in plasma protein extravasation after the AdVEGF-DΔNΔC treatment and a mild accumulation of pericardial effusate was observed at d6. However, AdVEGF-DΔNΔC also induced the growth of functional lymphatic vasculature, and the amount of pericardial fluid and level of vascular permeability had returned to normal by d21.Conclusion: Endovascular intramyocardial AdVEGF-DΔNΔC gene therapy proved to be safe and effective in the acute porcine myocardial infarction model and provides a new potential treatment option for patients with severe coronary heart disease.

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Section: Discussionmentioning

confidence: 99%

Adenoviral VEGF-DΔN ΔC gene therapy for myocardial ischemia

Pajula

Lähteenvuo

et al. 2022

Front. Bioeng. Biotechnol.

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“…Hence, although we did not observe any adverse changes in the tested endpoints indicative of arrhythmogenicity, we acknowledge that the study was unpowered to completely exclude the possible arrhythmia risk related to intramyocardial AdVEGF‐D GT. Moreover, despite RA patients being at high risk for major adverse cardiovascular events irrespective of the treatment, 8 it is worth noting that the observed favorable findings in HRV might also be explained by the fact that the study patients, including both AdVEGF‐D and control patients, were under careful supervision and their overall treatment was optimized during their participation in the trial, which might have translated into their better cardiac and overall health and better values in the HRV analysis. Even though a similar behavior in the frequency bands was not observed in the control group, this should also be interpreted with caution as a result of the low number of patients, particularly those who received placebo.…”

Section: Discussionmentioning

confidence: 99%

“…Although the primary purpose of KAT301 was to establish the safety and the feasibility of the treatment, the intervention was also found to increase myocardial perfusion reserve (MPR) assessed with 15 O‐H 2 O positron emission tomography (PET) and reduce angina symptoms (Canadian Cardiovascular Society class; CCS). Subsequently, intramyocardial AdVEGF‐D GT has been shown to be associated with a similar incidence of major adverse cardiovascular events and overall comorbidity than placebo during an 8‐year follow‐up 8 …”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, intramyocardial AdVEGF-D GT has been shown to be associated with a similar incidence of major adverse cardiovascular events and overall comorbidity than placebo during an 8-year follow-up. 8 Despite these encouraging results, concerns have been raised about the potential arrhythmogenic effects of therapies that are based on intramyocardially injected investigational medicinal products. Indeed, overexpression of VEGF-B 186 in mice hearts was reported to induce ventricular arrhythmias and increase the risk of sudden death in pigs.…”

Section: Introductionmentioning

confidence: 99%

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Intramyocardial adenoviral vascular endothelial growth factor‐D^∆N∆C gene therapy does not induce ventricular arrhythmias

Leikas

Hassinen

Kivelä

et al. 2022

The Journal of Gene Medicine

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Background: The phase I KAT301 trial investigated the use of intramyocardial adenoviral vascular endothelial growth factor-D ΔNΔC (AdVEGF-D) gene therapy (GT) to alleviate symptoms in refractory angina (RA) patients. In KAT301, 30 patients with RA were randomized to AdVEGF-D or the control group in 4:1 ratio. The treatment was found to be feasible, increasing myocardial perfusion and reducing angina symptoms at 1-year follow-up. However, there is some evidence suggesting that the intramyocardial delivery route and overexpression of (vascular endothelial growth) VEGFs might induce ventricular arrhythmias. Thus, we investigated whether intramyocardial AdVEGF-D GT increases the risk of ventricular arrhythmias in patients treated for RA.Methods: We analyzed non-invasive risk predictors of ventricular arrhythmias from 12-lead electrocardiography (ECG) as well as heart rate variability (HRV) and the incidence of arrhythmias from 24 h ambulatory ECG at baseline and 3 and 12 months after the GT. In addition, we analyzed the incidence of new-onset arrhythmias and pacemaker implantations during 8.2 years (range 6.3-10.4 years) of follow-up.Results: We found no significant increase in arrhythmias, including supraventricular and ventricular ectopic beats, atrial fibrillation, non-sustained ventricular tachycardias, and life-threatening tachycardias, nor changes in the non-invasive risk predictors of ventricular arrhythmias in the AdVEGF-D treated patients. Instead, we found a significant improvement in the very low and high-frequency bands of HRV suggestive of improved cardiac autonomic regulation after GT. Conclusions:In conclusion, our results suggest that AdVEGF-D GT does not predispose to arrhythmias and might improve HRV metrics.

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“…On the other hand, vascular normalization therapies, where increases in VEGF signaling would promote blood vessel growth or enhanced function, demonstrate their own challenges most typically related to delivery kinetics, administration routes, and ability to evaluate clinical outcomes (259)(260)(261). To address these challenges, some groups have begun investigating gene therapy as a technique to create a more sustained and controllable deliver of VEGF; an example of this is recent data from a clinical trial where VEGF-D delivered by adeno-associated viruses decreased angina associated symptoms in a majority of patients, with similar levels of major cardiac adverse events compared to control groups (262).…”

Section: Anti-vegf Treatments Side Effects and Efficacymentioning

confidence: 99%

Mechanoregulation of Vascular Endothelial Growth Factor Receptor 2 in Angiogenesis

Miller

Sewell-Loftin

2022

Front. Cardiovasc. Med.

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The endothelial cells that compose the vascular system in the body display a wide range of mechanotransductive behaviors and responses to biomechanical stimuli, which act in concert to control overall blood vessel structure and function. Such mechanosensitive activities allow blood vessels to constrict, dilate, grow, or remodel as needed during development as well as normal physiological functions, and the same processes can be dysregulated in various disease states. Mechanotransduction represents cellular responses to mechanical forces, translating such factors into chemical or electrical signals which alter the activation of various cell signaling pathways. Understanding how biomechanical forces drive vascular growth in healthy and diseased tissues could create new therapeutic strategies that would either enhance or halt these processes to assist with treatments of different diseases. In the cardiovascular system, new blood vessel formation from preexisting vasculature, in a process known as angiogenesis, is driven by vascular endothelial growth factor (VEGF) binding to VEGF receptor 2 (VEGFR-2) which promotes blood vessel development. However, physical forces such as shear stress, matrix stiffness, and interstitial flow are also major drivers and effectors of angiogenesis, and new research suggests that mechanical forces may regulate VEGFR-2 phosphorylation. In fact, VEGFR-2 activation has been linked to known mechanobiological agents including ERK/MAPK, c-Src, Rho/ROCK, and YAP/TAZ. In vascular disease states, endothelial cells can be subjected to altered mechanical stimuli which affect the pathways that control angiogenesis. Both normalizing and arresting angiogenesis associated with tumor growth have been strategies for anti-cancer treatments. In the field of regenerative medicine, harnessing biomechanical regulation of angiogenesis could enhance vascularization strategies for treating a variety of cardiovascular diseases, including ischemia or permit development of novel tissue engineering scaffolds. This review will focus on the impact of VEGFR-2 mechanosignaling in endothelial cells (ECs) and its interaction with other mechanotransductive pathways, as well as presenting a discussion on the relationship between VEGFR-2 activation and biomechanical forces in the extracellular matrix (ECM) that can help treat diseases with dysfunctional vascular growth.

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Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

Cited by 19 publications

References 22 publications

Adenoviral VEGF-DΔN ΔC gene therapy for myocardial ischemia

Adenoviral VEGF-DΔN ΔC gene therapy for myocardial ischemia

Intramyocardial adenoviral vascular endothelial growth factor‐D^∆N∆C gene therapy does not induce ventricular arrhythmias

Mechanoregulation of Vascular Endothelial Growth Factor Receptor 2 in Angiogenesis

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Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

Cited by 19 publications

References 22 publications

Adenoviral VEGF-DΔN ΔC gene therapy for myocardial ischemia

Adenoviral VEGF-DΔN ΔC gene therapy for myocardial ischemia

Intramyocardial adenoviral vascular endothelial growth factor‐D∆N∆C gene therapy does not induce ventricular arrhythmias

Mechanoregulation of Vascular Endothelial Growth Factor Receptor 2 in Angiogenesis

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Intramyocardial adenoviral vascular endothelial growth factor‐D^∆N∆C gene therapy does not induce ventricular arrhythmias