Adenoviral VEGF-B186R127S gene transfer induces angiogenesis and improves perfusion in ischemic heart.
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ABSTRACT:
SUBMITTER: Korpela H
PROVIDER: S-EPMC8666349 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aims:We evaluated for the first time the effects of angiogenic and lymphangiogenic AdVEGF-D?N?C gene therapy in patients with refractory angina. Methods and results:Thirty patients were randomized to AdVEGF-D?N?C (AdVEGF-D) or placebo (control) groups. Electromechanical NOGA mapping and radiowater PET were used to identify hibernating viable myocardium where treatment was targeted. Safety, severity of symptoms, quality of life, lipoprotein(a) [Lp(a)] and routine clinical chemistry were measured. Myocardial perfusion reserve (MPR) was assessed with radiowater PET at baseline and after 3- and 12-months follow-up. Treatment was well tolerated. Myocardial perfusion reserve increased significantly in the treated area in the AdVEGF-D group compared with baseline (1.00?±?0.36) at 3?months (1.31?±?0.46, P?=?0.045) and 12?months (1.44?±?0.48, P?=?0.009) whereas MPR in the reference area tended to decrease (2.05?±?0.69, 1.76?±?0.62, and 1.87?±?0.69; baseline, 3 and 12?months, respectively, P?=?0.551). Myocardial perfusion reserve in the control group showed no significant change from baseline to 3 and 12?months (1.26?±?0.37, 1.57?±?0.55, and 1.48?±?0.48; respectively, P?=?0.690). No major changes were found in clinical chemistry but anti-adenovirus antibodies increased in 54% of the treated patients compared with baseline. AdVEGF-D patients in the highest Lp(a) tertile at baseline showed the best response to therapy (MPR 0.94?±?0.32 and 1.76?±?0.41 baseline and 12?months, respectively, P?=?0.023). Conclusion:AdVEGF-D?N?C gene therapy was safe, feasible, and well tolerated. Myocardial perfusion increased at 1?year in the treated areas with impaired MPR at baseline. Plasma Lp(a) may be a potential biomarker to identify patients that may have the greatest benefit with this therapy.
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Project description:The therapeutic effects of ultrasonic microbubble transfection (UMT)-based vascular endothelial growth factor 165 (VEGF165) gene delivery on young and senescent endothelial progenitor cells (EPCs) were investigated. By UMT, plasmid DNA (pDNA) can be delivered into both young EPCs and senescent EPCs. In the UMT groups, higher pDNA-derived protein expression was found in senescent EPCs than in young EPCs. Consistent with this finding, a higher intracellular level of pDNA copy number was detected in senescent EPCs, with a peak at the 2-h time point post UMT. Ultrasonic microbubble delivery with or without VEGF improved the angiogenic properties, including the proliferation and/or migration activities, of senescent EPCs. Supernatants from young and senescent EPCs subjected to UMT-mediated VEGF transfection enhanced the proliferation and migration of human aortic endothelial cells (HAECs), and the supernatant of senescent EPCs enhanced proliferation more strongly than the supernatant from young EPCs. In the UMT groups, the stronger enhancing effect of the supernatant from senescent cells on HAEC proliferation was consistent with the higher intracellular VEGF pDNA copy number and level of protein production per cell in the supernatant from senescent cells in comparison to the supernatant from young EPCs. Given that limitations for cell therapies are the inadequate number of transplanted cells and/or insufficient cell angiogenesis, these findings provide a foundation for enhancing the therapeutic angiogenic effect of cell therapy with senescent EPCs in ischaemic cardiovascular diseases.
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Project description:Prevalence of left ventricular (LV) systolic and diastolic dysfunction increases with aging. We previously reported that urocortin 2 (Ucn2) gene transfer increases heart function in mice with heart failure with reduced ejection fraction. Here, we test the hypotheses that (1) Ucn2 gene transfer will increase LV function in aged mice and that (2) Ucn2 gene transfer given in early life will prevent age-related LV dysfunction. Nineteen-month-old (treatment study) and 3-month-old (prevention study) mice received Ucn2 gene transfer or saline. LV function was examined 3-4 months (treatment study) or 20 months (prevention study) after Ucn2 gene transfer or saline injection. In both the treatment and prevention strategies, Ucn2 gene transfer increased ejection fraction, reduced LV volume, increased LV peak -dP/dt and peak +dP/dt, and reduced global longitudinal strain. Ucn2 gene transfer-in both treatment and prevention strategies-was associated with higher levels of LV SERCA2a protein, reduced phosphorylation of LV CaMKIIa, and reduced LV ?-skeletal actin mRNA expression (reflecting reduced cardiac stress). In conclusion, Ucn2 gene transfer restores normal cardiac function in mice with age-related LV dysfunction and prevents development of LV dysfunction.
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Project description:Mechanisms of the transition from compensatory hypertrophy to heart failure are poorly understood and the roles of vascular endothelial growth factors (VEGFs) in this process have not been fully clarified. We determined the expression profile of VEGFs and relevant receptors during the progression of left ventricular hypertrophy (LVH). C57BL mice were exposed to transversal aortic constriction (TAC) and the outcome was studied at different time points (1 day, 2, 4, and 10 weeks). A clear compensatory phase (2 weeks after TAC) was seen with following heart failure (4 weeks after TAC). Interestingly, VEGF-C and VEGF-D as well as VEGF receptor-3 (VEGFR-3) were upregulated in the compensatory hypertrophy and VEGF-B was downregulated in the heart failure. After treatment with adeno-associated virus serotype 9 (AAV9)-VEGF-B(186) gene therapy in the compensatory phase for 4 weeks the function of the heart was preserved due to angiogenesis, inhibition of apoptosis, and promotion of cardiomyocyte proliferation. Also, the genetic programming towards fetal gene expression, a known phenomenon in heart failure, was partly reversed in AAV9-VEGF-B(186)-treated mice. We conclude that VEGF-C and VEGF-D are associated with the compensatory LVH and that AAV9-VEGF-B(186) gene transfer can rescue the function of the failing heart and postpone the transition towards heart failure.
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Project description:Previously, we demonstrated that intratumoral delivery of adenoviral vector encoding single-chain (sc)IL-23 (Ad.scIL-23) was able to induce systemic antitumor immunity. Here, we examined the role of IL-23 in diabetes in nonobese diabetic mice. Intravenous delivery of Ad.scIL-23 did not accelerate the onset of hyperglycemia but instead resulted in the development of psoriatic arthritis. Ad.scIL-23-treated mice developed erythema, scales, and thickening of the skin, as well as intervertebral disc degeneration and extensive synovial hypertrophy and loss of articular cartilage in the knees. Immunological analysis revealed activation of conventional T helper type 17 cells and IL-17-producing γδ T cells along with a significant depletion and suppression of T cells in the pancreatic lymph nodes. Furthermore, treatment with anti-IL-17 antibody reduced joint and skin psoriatic arthritis pathologies. Thus, these Ad.scIL-23-treated mice represent a physiologically relevant model of psoriatic arthritis for understanding disease progression and for testing therapeutic approaches.-Flores, R. R., Carbo, L., Kim, E., Van Meter, M., De Padilla, C. M. L., Zhao, J., Colangelo, D., Yousefzadeh, M. J., Angelini, L. A., Zhang, L., Pola, E., Vo, N., Evans, C. H., Gambotto, A., Niedernhofer, L. J., Robbins, P. D. Adenoviral gene transfer of a single-chain IL-23 induces psoriatic arthritis-like symptoms in NOD mice.
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Project description:Ischemic heart disease (IHD) is caused by the narrowing of arteries that work to provide blood, nutrients, and oxygen to the myocardial tissue. The worldwide epidemic of IHD urgently requires innovative treatments despite the significant advances in medical, interventional, and surgical therapies for this disease. Angiogenesis is a physiological and pathophysiological process that initiates vascular growth from pre-existing blood vessels in response to a lack of oxygen. This process occurs naturally over time and has encouraged researchers and clinicians to investigate the outcomes of accelerating or enhancing this angiogenic response as an alternative IHD therapy. Therapeutic angiogenesis has been shown to revascularize ischemic heart tissue, reduce the progression of tissue infarction, and evade the need for invasive surgical procedures or tissue/organ transplants. Several approaches, including the use of proteins, genes, stem/progenitor cells, and various combinations, have been employed to promote angiogenesis. While clinical trials for these approaches are ongoing, microvesicles and exosomes have recently been investigated as a cell-free approach to stimulate angiogenesis and may circumvent limitations of using viable cells. This review summarizes the approaches to accomplish therapeutic angiogenesis for IHD by highlighting the advances and challenges that addresses the applicability of a potential pro-angiogenic medicine.
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Project description:Gene targeting to tumors using adenoviral (Ad) vectors holds great potential for cancer imaging and therapy, but the limited efficacy of current methods used to improve delivery to target tissues and reduce unwanted interactions remain substantial barriers to further development. Progress in characterizing the set of molecular interactions used by Ad vectors to infect particular tissues has aided the development of novel strategies for retargeting vectors to tumor cells. One method is chemical retargeting of adenovirus using bispecific antibodies (bsAbs) against both viral capsid proteins and tumor-specific cell surface molecules. This approach can be combined either with competitive inhibitors designed to reduce viral tropism in undesired tissues, or with traditional therapeutics to increase the expression of surface molecules for improved tumor targeting. Ablating liver cell-specific interactions through mutation of capsid proteins or chemical means are promising strategies for reducing adenovirus-induced liver toxicity. The nature of tumor neovasculature also influences Ad delivery, and the use of vascular disrupting agents (VDAs) such as combretastatin can help elucidate these contributions. In this investigation, we evaluate a variety of these methods for retargeting Ad vectors to tumor cells in vitro and in vivo, and assess the contributions of specific molecular and tissue interactions that affect Ad transgene delivery.
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Project description:Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.
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Project description:Introduction: Many donor organs contain significant leukocyte reservoirs which upon transplantation activate recipient leukocytes to initiate acute rejection. We aimed to assess whether non-ischemic heart preservation via ex vivo perfusion promotes immunodepletion and alters the inflammatory status of the donor organ prior to transplantation. Methods: Isolated porcine hearts underwent ex vivo hypothermic, cardioplegic perfusion for 8 h. Leukocyte populations were quantified in left ventricle samples by flow cytometry. Cell-free DNA, cytokines, and chemokines were quantified in the perfusate. Tissue integrity was profiled by targeted proteomics and a histological assessment was performed. Heterotopic transplants comparing ex vivo hypothermic preservation and static cold storage were utilized to assess graft infiltration as a solid clinical endpoint. Results: Ex vivo perfusion significantly immunodepleted myocardial tissue. The perfusate displayed a selective, pro-inflammatory cytokine/chemokine pattern dominated by IFN-γ. The tissue molecular profile was improved following perfusion by diminished expression of nine pro-apoptotic and six ischemia-associated proteins. Histologically, no evidence of tissue damage was observed and cardiac troponin I was low throughout perfusion. Cell-free DNA was detected, the source of which may be necrotic/apoptotic leukocytes. Post-transplant graft infiltration was markedly reduced in terms of both leucocyte distribution and intensity of foci. Conclusions: These findings demonstrate that ex vivo perfusion significantly reduced donor heart immunogenicity via loss of resident leukocytes. Despite the pro-inflammatory cytokine pattern observed, a pro-survival and reduced ischemia-related profile was observed, indicating an improvement in graft viability by perfusion. Diminished graft infiltration was observed in perfused hearts compared with those preserved by static cold storage following 48 h of transplantation.
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Project description:Adenovirus serotype 5 remains one of the most promising vectors for delivering genetic material to cancer cells for imaging or therapy, but optimization of these agents to selectively promote tumor cell infection is needed to further their clinical development. Peptide sequences that bind to specific cell surface receptors have been inserted into adenoviral capsid proteins to improve tumor targeting, often in the background of mutations designed to ablate normal ligand:receptor interactions and thereby reduce off target effects and toxicities in non-target tissues. Different tumor types also express highly variable complements of cell surface receptors, so a customized targeting strategy using a particular peptide in the context of specific adenoviral mutations may be needed to achieve optimal efficacy. To further investigate peptide targeting strategies in adenoviral vectors, we used a set of peptide motifs originally isolated using phage display technology that evince tumor specificity in vivo. To demonstrate their abilities as targeting motifs, we genetically incorporated these peptides into a surface loop of the fiber capsid protein to construct targeted adenovirus vectors. We then systematically evaluated the ability of these peptide targeted vectors to infect several tumor cell types, both in vitro and in vivo, in a variety of mutational backgrounds designed to reduce CAR and/or HSG-mediated binding. Results from this study support previous observations that peptide insertions in the HI loop of the fiber knob domain are generally ineffective when used in combination with HSG detargeting mutations. The evidence also suggests that this strategy can attenuate other fiber knob interactions, such as CAR-mediated binding, and reduce overall viral infectivity. The insertion of peptides into fiber proved more effective for targeting tumor cell types expressing low levels of CAR receptor, as this strategy can partially compensate for the very low infectivity of wild-type adenovirus in those cells. Nevertheless, the incorporation of relatively low affinity peptide ligands into the fiber knob, while effective in vitro, has only minimal targeting efficacy in vivo and highlights the importance of high affinity ligand:receptor interactions to achieve tumor targeting.
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