Progress and prospects: hurdles to cardiovascular gene therapy clinical trials

Hedman, Marja; Hartikainen, Juha; Ylä‐Herttuala, Seppo

doi:10.1038/gt.2011.43

Cited by 57 publications

(35 citation statements)

References 46 publications

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“…Adenoviruses have been used extensively in humans (www.wiley.co.uk/genetherapy), including for cardiovascular disease. 30 As such, the safety profile of vascular gene therapy is also favorable for the translation of AdTIMP-3 gene therapy. A further important safety consideration is that excess virus will be washed from the graft before bypass grafting, thereby further reducing the viral load on the patient.…”

Section: George Et Al Timp-3 Gene Therapy For Vein Grafts S139mentioning

confidence: 99%

Sustained Reduction of Vein Graft Neointima Formation by Ex Vivo TIMP-3 Gene Therapy

George

Wan

et al. 2011

Circulation

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Background— Coronary artery vein graft failure, resulting from thrombosis, intimal thickening, and atherosclerosis, is a significant clinical problem, with approximately 50% of vein grafts failing within 10 years. Intimal thickening is caused by migration of vascular smooth muscle cells from the media to the intima, where they proliferate. Interventions using gene transfer to inhibit vascular smooth muscle cells proliferation and migration are attractive because ex vivo access to the graft is possible. The involvement of matrix-degrading metalloproteinases in intimal thickening is well established, and we previously showed that adenoviral-delivered overexpression of an endogenous inhibitor, the tissue inhibitor of metalloproteinases-3 (TIMP-3), significantly retarded intimal thickening in short-term autologous porcine arteriovenous interposition grafts (28 days). However, it is essential to determine whether this approach will provide longer-term benefits. Methods and Results— We assessed whether a recombinant adenovirus that overexpresses TIMP-3 (RAdTIMP-3) affects vein graft intimal thickening in the longer term (at 3 months). Porcine saphenous veins were subjected to luminal infection with 2.5×10 10 pfu/mL RAdTIMP-3 or RAd60 (control virus) or vehicle control, for 30 minutes before implantation into the carotid artery. Analysis of grafts harvested 3 months after delivery revealed that RAdTIMP-3–infected grafts had significantly reduced intimal areas compared with both controls (3.2±0.4 mm 2 versus 5.6±0.7 mm 2 and 5.9±0.5 mm 2 , RAdTIMP-3, RAd60, and vehicle, respectively). Medial areas were also significantly decreased by TIMP-3 (3.8±0.3 mm 2 versus 6.7±1.0 mm 2 and 5.2±0.4 mm 2 , RAdTIMP-3, RAd60, and vehicle, respectively). Conclusions— Overexpression of TIMP-3 provides a sustained retardation of vein graft intimal thickening and highlights the translational potential for ex vivo TIMP-3 gene therapy.

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Section: George Et Al Timp-3 Gene Therapy For Vein Grafts S139mentioning

confidence: 99%

Sustained Reduction of Vein Graft Neointima Formation by Ex Vivo TIMP-3 Gene Therapy

George

Wan

et al. 2011

Circulation

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“…Importantly, while preclinical models and gene therapy trials performed without controls that have tested angiogenic factors have shown positive effects, randomized clinical trials with placebo-control groups have led to inconclusive and clinically irrelevant results. The lack of efficacy in proangiogenic trials suggests that growth factor concentration does not reach the appropriate dose or does not exert its effect long enough to result in a significant angiogenic effect [27].…”

Section: Gene Therapymentioning

confidence: 99%

Cardiac Regeneration with Stem Cells

Pelacho

Mazo

Montori

et al. 2012

Regenerative Medicine and Cell Therapy

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Cardiovascular diseases (CVD) are the main causes of morbidity and mortality worldwide. A huge effort has been made to improve current standard approaches for treating patients with ischemic heart disease. However, despite the greater efficacy of new drugs and clinical techniques, which have decreased the number of acute patients and prolonged the life of chronic ones, the classic treatments are still not able to regenerate the diseased heart. For this reason, alternative therapies based on the use of gene, protein, and stem cells have been developed in combination with bioengineering techniques, with the aim not only of protecting but also repairing the damaged heart. All these new therapies, especially stem cell therapy and the possibility of combining these cells with biomaterials in order to reinforce their potential or even create new tissues, are reviewed in this chapter. Abbreviations AAVAdeno-associated virus ADSC

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“…Although there have been some improvements in angina class and stress sestamibi scans, none of the randomized controlled Phase II/III trials have demonstrated clinically relevant positive effects [56,57]. The most likely reason for this apparent discrepancy may be related to the placebo effect, patient selection and ineffective gene expression [57]. The efficacy of FGF to promote angiogenesis has been well established in an animal model of coronary ischemia.…”

Section: Clinical Trialsmentioning

confidence: 99%

“…This problem is multifaceted. First, many clinical trials were carried out with nonviral or short-term efficacy virus vectors, and the protocols used a single-dose method of delivery [57]. Second, techniques of gene delivery applied in clinical trials were simple without attempts to limit collateral expression or to extend vector residence time, overcome the endothelial barrier or to utilize retrograde transcoronary transfer [3].…”

Section: Clinical Trialsmentioning

confidence: 99%

The Road Ahead: Working Towards Effective Clinical Translation of Myocardial Gene Therapies

et al. 2013

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During the last two decades the fields of molecular and cellular cardiology, and more recently molecular cardiac surgery, have developed rapidly. The concept of delivering cDNA encoding a therapeutic gene to cardiomyocytes using a vector system with substantial cardiac tropism, allowing for long-term expression of a therapeutic protein, has moved from hypothesis to bench to clinical application. However, the clinical results to date are still disappointing. The ideal gene transfer method should be explored in clinically relevant animal models of heart disease to evaluate the relative roles of specific molecular pathways in disease pathogenesis, helping to validate the potential targets for therapeutic intervention. Successful clinical cardiovascular gene therapy also requires the use of nonimmunogenic cardiotropic vectors capable of expressing the requisite amount of therapeutic protein in vivo and in situ. Depending on the desired application either regional or global myocardial gene delivery is required. Cardiac-specific delivery techniques incorporating mapping technologies for regional delivery and highly efficient methodologies for global delivery should improve the precision and specificity of gene transfer to the areas of interest and minimize collateral organ gene expression.

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Progress and prospects: hurdles to cardiovascular gene therapy clinical trials

Cited by 57 publications

References 46 publications

Sustained Reduction of Vein Graft Neointima Formation by Ex Vivo TIMP-3 Gene Therapy

Sustained Reduction of Vein Graft Neointima Formation by Ex Vivo TIMP-3 Gene Therapy

Cardiac Regeneration with Stem Cells

The Road Ahead: Working Towards Effective Clinical Translation of Myocardial Gene Therapies

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