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Seppo Ylaherttuala - One of the best experts on this subject based on the ideXlab platform.
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advances and challenges in Cardiovascular Gene Therapy
Human Gene Therapy, 2017Co-Authors: Johanna Lahteenvuo, Seppo YlaherttualaAbstract:Many promising Cardiovascular Gene Therapy approaches have failed to fulfill expectations in clinical trials. However, 20 years of research and method development has laid a solid groundwork for future therapies, and the need for new treatment options still exists. The safety of Gene Therapy has been established with various viral vectors, transGenes and delivery methods. Improving success in clinical settings requires careful consideration of the translational process. This requires both improving animal models and preclinical end points, and new approach in patient recruitment and selection of clinical end points. This review focuses on bidirectional translationality from bench to bedside and back and proposes ways to improve the process. Developing a highly complex new Therapy has taken an enormous amount of work and resources, but perhaps now after the hard lessons Cardiovascular Gene Therapy is ready become a clinical reality.
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Cardiovascular Gene Therapy past present and future
Molecular Therapy, 2017Co-Authors: Seppo Ylaherttuala, Andy BakerAbstract:Cardiovascular diseases remain a large global health problem. Although several conventional small-molecule treatments are available for common Cardiovascular problems, Gene Therapy is a potential treatment option for acquired and inherited Cardiovascular diseases that remain with unmet clinical needs. Among potential targets for Gene Therapy are severe cardiac and peripheral ischemia, heart failure, vein graft failure, and some forms of dyslipidemias. The first approved Gene Therapy in the Western world was indicated for lipoprotein lipase deficiency, which causes high plasma triglyceride levels. With improved Gene delivery methods and more efficient vectors, together with interventional transGene strategies aligned for a better understanding of the pathophysiology of these diseases, new approaches are currently tested for safety and efficacy in clinical trials. In this article, we integrate a historical perspective with recent advances that will likely affect clinical development in this research area.
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28 animal models of Gene Therapy for Cardiovascular disease
Adenoviral Vectors for Gene Therapy (Second Edition), 2016Co-Authors: Johanna P Laakkonen, Seppo YlaherttualaAbstract:Cardiovascular Gene Therapy can be used to grow neovessels into ischemic tissues, reduce neointimal hyperplasia, improve cardiomyocyte function, and to treat hypertension and dyslipidemias. Human adenovirus (Ad) serotypes 2 and 5 are commonly used vectors in clinical trials because of their high Gene transfer efficiency, ease of production, and well-known virus–cell biology. Ad vectors can be administrated to tissues via intramyocardial and intramuscular injections, coronary infusion, and pericardial or systemic delivery. Delivery method, serotype, and vector dosage are critical determinants of the therapeutic outcome. Animal models for Cardiovascular diseases (CVDs) are essential in order to develop new therapeutic strategies. Increased understanding of the pathoGenesis of CVDs enables identification of novel molecular targets for Therapy. In the following chapter, methods and animal models used for Gene Therapy of CVDs are described in the context of Ad vector–mediated transGene delivery.
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Cardiovascular Gene Therapy with vascular endothelial growth factors
Gene, 2013Co-Authors: Seppo YlaherttualaAbstract:Abstract Therapeutic angioGenesis with vascular endothelial growth factors (VEGFs) is a promising approach for the treatment of ischemic myocardium and peripheral skeletal muscles. Preclinical studies in large animals have clearly demonstrated safety and efficacy of VEGF Gene Therapy in clinically relevant disease models. However, first clinical trials with intravascular delivery of VEGF vector constructs have only resulted in limited benefits to the patients. Second Generation VEGF-based Gene Therapy trials are based on direct intramyocardial and intraskeletal muscle injections in order to achieve better transfection efficiency and more targeted effects. Phase I/II studies are currently ongoing to test safety, feasibility and efficacy of these improved approaches in patients with severe Cardiovascular diseases.
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arteriogenic Therapy based on simultaneous delivery of vegf a and fgf4 Genes improves the recovery from acute limb ischemia
Vascular Cell, 2013Co-Authors: Agnieszka Jazwa, Seppo Ylaherttuala, Mateusz Tomczyk, Hevidar Taha, Elisa Hytonen, Mateusz Stoszko, Lorena Zentilin, Mauro Giacca, Costanza Emanueli, Alicja JozkowiczAbstract:Gene Therapy stimulating the growth of blood vessels is considered for the treatment of peripheral and myocardial ischemia. Here we aimed to achieve angiogenic synergism between vascular endothelial growth factor-A (VEGF-A, VEGF) and fibroblast growth factor 4 (FGF4) in murine normoperfused and ischemic limb muscles. Adeno-associated viral vectors (AAVs) carrying β-galactosidase Gene (AAV-LacZ), VEGF-A (AAV-VEGF-A) or two angiogenic Genes (AAV-FGF4-IRES-VEGF-A) were injected into the normo-perfused adductor muscles of C57Bl/6 mice. Moreover, in a different experiment, mice were subjected to unilateral hindlimb ischemia by femoral artery ligation followed by intramuscular injections of AAV-LacZ, AAV-VEGF-A or AAV-FGF4-IRES-VEGF-A below the site of ligation. Post-ischemic blood flow recovery was assessed sequentially by color laser Doppler. Mice were monitored for 28 days. VEGF-A delivered alone (AAV-VEGF-A) or in combination with FGF4 (AAV-FGF4-IRES-VEGF-A) increased the number of capillaries in normo-perfused hindlimbs when compared to AAV-LacZ. Simultaneous overexpression of both agents (VEGF-A and FGF4) stimulated the capillary wall remodeling in the non-ischemic model. Moreover, AAV-FGF4-IRES-VEGF-A faster restored the post-ischemic foot blood flow and decreased the incidence of toe necrosis in comparison to AAV-LacZ. Synergy between VEGF-A and FGF4 to produce stable and functional blood vessels may be considered a promising option in Cardiovascular Gene Therapy.
Bruce C Trapnell - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of adenoviral vector mediated Gene delivery to vascular smooth muscle cells modulation by poloxamer 407 and implications for Cardiovascular Gene Therapy
Human Gene Therapy, 1995Co-Authors: Keith L March, Julia Madison, Bruce C TrapnellAbstract:Regional in vivo delivery of therapeutic Genes to the Cardiovascular system at sites of localized vascular disease is feasible by catheter-mediated delivery of recombinant adenoviral vectors. Vascular smooth muscle cell (SMC) proliferation, which follows angioplasty and contributes to restenosis, is one process that may be amenable to such a Gene Therapy strategy. The clinical utility of localized delivery strategies such as this critically depends upon successful Gene transfer to sufficient numbers of vascular cells, locally, within a clinically acceptable time period. Relatively limited information is available concerning the kinetics of Gene transfer by first-Generation, replication-deficient, recombinant adenovirus (Av1) vectors. In this context, we evaluated the pharmacokinetics of adenoviral vector-mediated Gene delivery to vascular SMC using an Av1 reporter vector (Av1LacZ4) expressing a nuclear-targeted beta-galactosidase (beta-Gal) reporter. Bovine aortic SMC were exposed to Av1LacZ4 for various times at a range of concentrations and multiplicities of infection (MOI). After exposure, cells were washed and evaluated for transduction at 48 hr by X-Gal staining. Transduction occurred with a rate constant typically determined in the range of 10(-10) to 10(-11) events.ml/cell.virion.min. The rate of transduction was directly dependent on virion concentration, but not substantially on the virion-to-cell ratio. Relatively low fractions of the total input vector were found to be consumed, even after prolonged adsorption times. We hypothesized that the cellular transduction rate (and thus overall efficiency) would be improved by agents that could maintain a prolonged, high pericellular vector concentration. To evaluate this, cells were exposed to the vector in the presence of 15 grams/dl poloxamer 407, a viscous biocompatibile polyol, for various times followed by washout and evaluation as described above. Both cells and vector remained viable under these conditions, and poloxamer was found to increase the apparent transduction rate 10-fold or more (1-5 x 10(-9) transduction events.ml/cell.virion.min), with remarkable increases in numbers of cells transduced even after brief exposure periods. These observations demonstrate that the pharmacokinetics of adenoviral-mediated Gene delivery to vascular SMC can be modulated by agents such as poloxamer 407, which may improve Gene delivery by maintaining high pericellular concentrations of vector. Such modulation may permit achievement of desired levels of Gene transfer while requiring lower total viral dosage and exposure time, and in turn may have important implications for in vivo Gene delivery to vascular tissues.
Behzad Baradaran - One of the best experts on this subject based on the ideXlab platform.
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construction and development of a cardiac tissue specific and hypoxia inducible expression vector
Advanced Pharmaceutical Bulletin, 2018Co-Authors: Shahrooz Ghaderi, Neda Alidadiani, Jafar Soleimani Rad, Hamid Reza Heidari, Nafi Dilaver, Behzad Mansoori, Reza Rhabarghazi, Rezayat Parvizi, Vahid Khaze Shahgoli, Behzad BaradaranAbstract:Purpose: Cardiovascular Gene Therapy is a sophisticated approach, thanks to the safety of vectors, stable transGene expression, delivery method, and different layers of the heart. To date, numerous expression vectors have been introduced in biotechnology and biopharmacy industries in relation to Genetic manipulation. Despite the rapid growth of these modalities, they must be intelligently designed, addressing the cardiac-specific transGene expression and less side effects. Herein, we conducted a pilot project aiming to design a cardiac-specific hypoxia-inducible expression cassette. Methods: We explored a new approach to design an expression cassette containing cardiac specific enhancer, hypoxia response elements (HRE), cardiac specific promoter, internal ribosome entry site (IRES), and beta globin poly A sequence to elicit specific and inducible expression of the Gene of interest. Enhanced green fluorescent protein (eGFP) was sub-cloned by BglII and NotI into the cassette. The specificity and inducible expression of the cassette was determined in both mouse myoblast C2C12 and mammary glandular tumor 4T1 as 'twin' cells. eGFP expression was evaluated by immunofluorescence microscope and flow cytometry at 520 nm emission peak. Results: Our data revealed that the designed expression cassette provided tissue specific and hypoxia inducible (O2<1%) transGene expression. Conclusion: It is suggested that cardiac-specific enhancer combined with cardiac-specific promoter are efficient for myoblast specific Gene expression. As well, this is for the first time that HRE are derived from three well known hypoxia-regulated promoters. Therefore, there is no longer need to overlap PCR process for one repeated sequence just in one promoter.
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Construction and Development of a Cardiac Tissue-Specific and Hypoxia-Inducible Expression Vector
Tabriz University of Medical Sciences, 2018Co-Authors: Shahrooz Ghaderi, Neda Alidadiani, Jafar Soleimani Rad, Hamid Reza Heidari, Nafi Dilaver, Behzad Mansoori, Reza Rhabarghazi, Rezayat Parvizi, Vahid Khaze Shahgoli, Behzad BaradaranAbstract:Purpose: Cardiovascular Gene Therapy is a sophisticated approach, thanks to the safety of vectors, stable transGene expression, delivery method, and different layers of the heart. To date, numerous expression vectors have been introduced in biotechnology and biopharmacy industries in relation to Genetic manipulation. Despite the rapid growth of these modalities, they must be intelligently designed, addressing the cardiac-specific transGene expression and less side effects. Herein, we conducted a pilot project aiming to design a cardiac-specific hypoxia-inducible expression cassette. Methods: We explored a new approach to design an expression cassette containing cardiac specific enhancer, hypoxia response elements (HRE), cardiac specific promoter, internal ribosome entry site (IRES), and beta globin poly A sequence to elicit specific and inducible expression of the Gene of interest. Enhanced green fluorescent protein (eGFP) was sub-cloned by BglII and NotI into the cassette. The specificity and inducible expression of the cassette was determined in both mouse myoblast C2C12 and mammary glandular tumor 4T1 as ‘twin’ cells. eGFP expression was evaluated by immunofluorescence microscope and flow cytometry at 520 nm emission peak. Results: Our data revealed that the designed expression cassette provided tissue specific and hypoxia inducible (O2
Andy Baker - One of the best experts on this subject based on the ideXlab platform.
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Cardiovascular Gene Therapy past present and future
Molecular Therapy, 2017Co-Authors: Seppo Ylaherttuala, Andy BakerAbstract:Cardiovascular diseases remain a large global health problem. Although several conventional small-molecule treatments are available for common Cardiovascular problems, Gene Therapy is a potential treatment option for acquired and inherited Cardiovascular diseases that remain with unmet clinical needs. Among potential targets for Gene Therapy are severe cardiac and peripheral ischemia, heart failure, vein graft failure, and some forms of dyslipidemias. The first approved Gene Therapy in the Western world was indicated for lipoprotein lipase deficiency, which causes high plasma triglyceride levels. With improved Gene delivery methods and more efficient vectors, together with interventional transGene strategies aligned for a better understanding of the pathophysiology of these diseases, new approaches are currently tested for safety and efficacy in clinical trials. In this article, we integrate a historical perspective with recent advances that will likely affect clinical development in this research area.
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1057 Generating efficient promoters for Cardiovascular Gene Therapy using synthetic promoter libraries
Molecular Therapy, 2005Co-Authors: Stuart A Nicklin, Anna F Dominiczak, Andy BakerAbstract:Optimised promoters would be beneficial to maximise long-term transGene expression in vivo and improve Gene Therapy efficiency. Viral promoters can achieve high-level constitutive transGene expression in most mammalian cell types, however they are non-selective and sensitive to silencing in vivo via methylation, hampering efficacy for long-term expression of certain transGenes. Candidate mammalian promoters have been investigated as possible alternatives for cell-selective transcription, however many produce low-level transcriptional activity, or their size precludes their insertion into viral Gene delivery vectors. We are developing synthetic promoter elements via the rational design and random combination of transcriptional regulating elements (TREs) linked to a basal promoter element for regulated transcription in skeletal or cardiac muscle under conditions of oxidative stress, a significant pathophysiological phenomenon that contributes to the development of varied Cardiovascular diseases.
Edith Tzeng - One of the best experts on this subject based on the ideXlab platform.
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the emerging role of Gene Therapy in the treatment of Cardiovascular diseases
Critical Reviews in Clinical Laboratory Sciences, 2003Co-Authors: Joel E Barbato, Melina R Kibbe, Edith TzengAbstract:Cardiovascular disease is the number one source of morbidity and mortality in the United States. Therapies directed at a variety of Cardiovascular diseases have blossomed over the last several decades. The advent of Gene Therapy, first as an intriguing tool, and subsequently with the early successes of Gene trials involving the treatment of SCID, led to the development of Gene Therapy as a potentially exciting and viable Therapy in Cardiovascular diseases. A variety of novel vector technologies and delivery systems have been developed to more efficiently deliver the Gene product to the desired organ or tissue bed. Early clinical trials focused on stimulating angioGenesis. Subsequently, a number of other aspects of Cardiovascular disease have been identified as potential targets for Gene Therapy, including the prevention of restenosis, the prevention and treatment of thrombosis, and the prevention of transplant vasculopathy. With over forty clinical human trials either completed or currently enrolling, Cardiovascular Gene Therapy has proven to be safe and initial results suggest its efficacy.
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optimizing Cardiovascular Gene Therapy increased vascular Gene transfer with modified adenoviral vectors
Archives of Surgery, 2000Co-Authors: Melina R Kibbe, Alan D Murdock, Thomas J Wickham, Alena Lizonova, Imre Kovesdi, Suhua Nie, Larry L Shears, Timothy R Billiar, Edith TzengAbstract:Background Adenovirus is widely used as a vector for Gene transfer to the vasculature. However, the efficiency of these vectors can be limited by ineffective viral-target cell interactions. Viral attachment, which largely determines adenoviral tropism, is mediated through binding of the adenoviral fiber coat protein to the Coxsackievirus and adenovirus receptor, while internalization follows binding of the adenoviral RGD motif to α v -integrin receptors. Modifications of the fiber coat protein sequence have been successful for targeting the adenovirus to more prevalent receptors in the vasculature, including heparan sulfate–containing receptors and α v -integrin receptors. Hypothesis Modified adenoviral vectors targeted to receptors more prevalent in the vasculature result in an increased transfer efficiency of the virus in vitro and in vivo even in the presence of clinically relevant doses of heparin. Design We tested 2 modified E1- and E3-deleted Ad5 type adenoviral vectors containing the β-galactosidase Gene. AdZ.F(pK7) contains multiple positively charged lysines in the fiber coat protein that target the adenovirus to heparan sulfate receptors, while AdZ.F(RGD) contains an RGD integrin-binding sequence in the fiber coat protein that allows binding to α v -integrin receptors. The Gene transfer efficiency of these modified viruses was compared in rat aortic smooth muscle cells in vitro and in an in vivo porcine model of balloon-induced arterial injury. Because of the use of heparin during most vascular surgical procedures and the concern that heparin might interfere with the binding of AdZ.F(pK7) to heparan sulfate receptors, the effect of heparin on the in vitro and in vivo transfer efficiency of these 2 modified adenoviruses was evaluated. Results In vitro infection of rat aortic smooth muscle cells with AdZ.F(pK7) and AdZ.F(RGD) resulted in significantly higher levels of β-galactosidase expression compared with the unmodified adenovirus (mean ± SEM, 1766.3 ± 89.1 and 44.8 ± 3.4 vs 10.1 ± 0.7 mU per milligram of protein; P P Conclusions Modifications of the adenovirus that lead to receptor targeting resulted in significantly improved Gene transfer efficiencies. These improvements in transfer efficiencies observed with the modified vectors decreased slightly in the presence of heparin. However, AdZ.F(pK7) was still superior to AdZ.F(RGD) and AdZ.F despite heparin administration. These data demonstrate that modifications of adenoviral vectors that enhance binding to heparan sulfate receptors significantly improve Gene transfer efficiency even in the presence of heparin and suggest an approach to optimize Gene transfer into blood vessels.