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From centenarians' genetic code, a potential new therapy against cardiovascular diseases 9 hours ago. Jul 09, Jul 03, New high blood pressure guidelines could increase detection of gestational hypertension Jul 03, User comments. Oct 03, Switch one gene off and there's no heart. Switch another off and there's a dispersion of cells.
Exactly how did the first heart "evolve" given these absolutely critical gene functionality? Here I'm thinking of the genes that control the shape of the heart, the construction of chambers in the correct place and of the correct size and the placement of the correct pulsing cells at the right place connected to the right nerves etc. We did not evolve, we were designed and created by the ultimate super intelligent being otherwise known as God.
Report Block. Sign in. Forgot Password Registration. What do you think about this particular story? Your message to the editors. Your email only if you want to be contacted back. Send Feedback. E-mail the story World-wide study reveals new genes for heart function. Your friend's email. Your email. I would like to subscribe to Science X Newsletter. Learn more. Your name. Instead, only the most salient features and controversies relevant to the subsequent clinical trials see below will be highlighted.
Several types of angiogenic factors that exhibit different properties have been explored in gene therapy for CVD. VEGF-A Specific interaction between these VEGF subtypes and their cognate cellular receptors evokes a differential cellular response in endothelial cells and cardiomyocytes. Simultaneously, activation of VEGFR2 in newly formed cardiomyocytes increased expression of anti-apoptotic proteins and reduced expression of pro-apoptotic proteins, suggesting a direct effect on cardiomyocytes.
In normal flow conditions, VEGF response is characterized by dilatation of the existing capillaries. In contrast, in an ischaemic situation, a more robust angiogenic response is observed. Angiogenic factors in gene therapy for CVD. Description of the membrane receptor involved in the angiogenic factor pathways and the physiological effects.
Studies in small and large animal ischaemic heart disease models have reported that myocardial overexpression of VEGF following naked DNA transfection, Ad vectors, or AAV transduction induce angiogenesis, improving myocardial blood flow and overall left ventricular function. Ang 1. For instance, direct intramyocardial injection of AAV expressing VEGF and Ang1 resulted in activation of pro-survival pathways and reduction of cell apoptosis, consistent with improvement in the perfusion and function of the heart in a porcine MI model.
FGF induces cell proliferation, migration, and production of proteases in endothelial cells and cardiomyocytes. Additionally, interaction of FGF5 with cardiomyocytes has been reported to stimulate angiogenesis, enhance collateral blood flow, and relieve stress-induced ischaemia. These preclinical studies justified the use of angiogenic gene therapy in clinical trials see below.
Nevertheless, despite their promise, angiogenic gene therapies suffered several limitations: i an increase of vascular permeability was often apparently raising important safety concerns i. Nevertheless, careful selection of the type of angiogenic factor used may mitigate some of these risks i.
The main objective of these trials is to promote the development of collateral blood vessels in ischaemia-related conditions, such as chronic critical limb ischaemia, myocardial ischaemia, angina, or peripheral arterial occlusive disease. The study reported functional and symptomatic improvements in patients, but without any significant difference in perfusion compared with placebo.
The plasmid was administered through an endocardial route using an electro-anatomical guidance catheter in patients with Class 3 or 4 angina. After 6 months of follow-up, no evidence of improvement was observed in myocardial perfusion assessed by single-photon emission tomography SPECT. In an effort to improve the gene delivery efficiency of the angiogenic factors, viral vectors were used instead. VEGF-A in patients with severely symptomatic coronary artery disease who are not candidates for conventional revascularization.
Though one of the primary endpoints of the trial, exercise treadmill evaluation was significantly improved after 6 months of follow-up, there was no evidence of improvement in myocardial perfusion, evaluated by SPECT. Different limitations inherent to the study such as the surgical vector delivery technique employed, lack of blindness for the treatment groups, and the advances in catheter systems for percutaneous intramyocardial delivery prompted new clinical studies. Using a catheter-mediated trans -endocardial injection strategy, patients with coronary heart disease CHD with no other therapeutic options will be recruited in an escalating dose protocol.
VEGF-D will be injected into 10 myocardial sites. These trials constitute the major advances in VEGF-based gene therapy. Selected patients with chronic stable angina exhibited symptomatic improvement in exercise time at 4 weeks after injection, and the overall safety profile of the viral vector system was ascertained. After 8 weeks of follow-up, a trend towards improvement in stress-induced myocardial perfusion was observed compared with baseline.
Nonetheless, there was no significant difference compared with the placebo group. The results demonstrated a sex-specific beneficial effect on the exercise treadmill test; however, this effect was mainly due to a poor placebo response among women. Several factors could have influenced the negative results obtained in the clinical trials using angiogenic factors compared with the promising preclinical data or earlier clinical trials.
This suggested a strong placebo effect, in part due to the strict selection of patients, the delivery method used intramuscular injection can increase the production of growth factors , or a possible bias by lack of a blinded protocol. The lack of efficacy could also be explained by the fact that the patients selected for clinical trials were in end stages of the disease, with the more severe presentation, despite previous pharmacological interventions.
It cannot be excluded that these angiogenic gene therapies may be more effective in the less severe patients, which constitutes the higher percentage of patients in the population. Finally, especially for naked plasmid strategies, the poor DNA uptake of cardiac and muscle cells is low, the short transient expression limited up to 2 weeks can be insufficient for achieve an effective angiogenic stimulus with substantial quantifiable changes in the heart parameter in comparison to the results obtained in preclinical models.
Given the intrinsic complexity of angiogenesis, it is unlikely that administration of a single gene would suffice to obtain sustainable effects in patients with CVD. Indeed, preclinical studies have shown that additional factors are needed to lead to optimal endothelial and smooth cell proliferation and integration into sustainable and functional blood vessel development.
Cardiovascular genetics - Latest research and news | Nature
Most importantly, SERCA2a gene transfer improves contractile function survival rates and the energy potential in failing hearts without increasing mortality or worsening metabolism. Bax and apoptotic and inflammatory e. LV containing the SERCA2 gene were delivered by a hypothermic intracoronary delivery method in rat myocardium, 2 weeks after MI, Significantly, this LV-SERCA2 gene therapy resulted in long-term improvement of systolic and diastolic function, prevention of left ventricular remodelling even up to 6 months after gene therapy, consistent with significant improvement of the survival rate.
SA1 is preferentially expressed in myocardial tissue though low levels have also been reported in other tissues.
Cardiomyocytes that overexpress SA1 present a higher ATP content than control cells, suggesting a role for SA1 in energy metabolism. Pleger et al. The results demonstrated long-term improvement in cardiac dysfunction and attenuated left ventricular remodelling. Even non-transduced cardiomyocytes showed a trend towards functional improvement, suggesting that SA1-overexpressing cardiomyocytes have an indirect bystander effect on neighbouring cardiomyocytes.
Retrograde coronary venous delivery strategy was used in post-ischaemic pig model of HF after 2 weeks of occlusion of the left circumflex coronary artery. The follow-up resulted in long-term benefits in cardiac performance by improving mitochondrial function in failing cardiomyocytes and reverse remodelling by improving systolic and diastolic left ventricular performance at 12 weeks post intervention. An Ad vector encoding SA1 was used to transduce cardiomyocytes isolated from the heart of patients undergoing transplant surgery.
SA1 levels returned to normal in transduced cardiomyocytes, with clear improvement in contractibility performance and restoring of sarcoplasmic reticulum functions. These preclinical data support the use of SA1 as a gene therapy modality in patients with HF. This AC6 pathway also results in the transcription factordependent suppression of PLN promoter activity.
The overall effect of PLN activation is a decrease in contractility and the rate of muscle relaxation, thereby decreasing stroke volume and heart rate. Indeed, studies in transgenic mice overexpressing AC6 demonstrated increased cAMP generation in cardiomyocytes, which in turn triggered an improvement in cardiac function, particularly left ventricular contractile function.
Nevertheless, AC6 overexpression in a long-term murine model of pressure-overload HF was correlated with a worse outcome, possibly because of increased systolic ventricular wall stress. These results suggest a different molecular imbalance depending on the cause of the HF. These results were associated with increased cAMP-generating capacity. Moreover, intracoronary delivery of AC6 in small and large preclinical models confirms its favourable safety profile. Homologous desensitization reduces the neurohormonal response in the heart, which leads to worsening heart function during HF.
The results also suggest a correction of the catecholaminergic overdrive in post-MI HF. After 12 months of follow-up, improvement or stabilization was reported based on the Heart Failure Questionnaire, a 6-min walk test, peak maximum oxygen consumption, N-terminal pro-hormone brain natriuretic peptide levels, and left ventricular end-systolic volume. The first results are expected in mid The first results are expected at the beginning of The secondary endpoint comparison of the AAV1-SERCA2a vector to placebo, defined as all-cause death, heart transplant or need for a mechanical circulatory support device, likewise failed to show a significant treatment effect.
All other exploratory efficacy endpoints improvement in NYHA classification, 6-min Walk Test, and Quality of Life were also inconsistent with a treatment effect. No safety issues were noted, however. The exact reason for this outcome is not fully understood, and further studies are required to assess the efficiency of cardiac gene delivery using qPCR analysis on available patient biopsies. Intracoronary delivery of the AAV1 vector may not have resulted in efficient transduction of cardiomyocytes.
This may reflect the relatively low transduction efficiencies in cardiomyocytes after anterograde delivery with AAV1-SERCA2a in porcine models, 91 , consistent with the relatively low vector copy number determined by qPCR. Moreover, the presence of vector DNA in the myocardium does not necessarily imply bona fide gene transduction. In the CUPID2 trial, the vectors were administered by anterograde coronary delivery without any vessel balloon occlusion. The main advantage of this delivery strategy is that it does not increase the risk of ischaemic events in an already functionally compromised heart.
However, under those circumstances the vector rapidly disseminates via the circulation into distal tissues, diminishing the overall efficacy of cardiac transduction. Consequently, vector dissemination may result in the inadvertent transduction of non-target tissues, particularly the liver. The use of retrograde delivery methods may potentially increase cardiac transduction efficiencies. Five different doses ranging from 3.
After 12 weeks of follow-up, patients will undergo exercise treadmill testing, and left ventricular functional parameters will be examined by echocardiography before and during the isoproterenol test. The progress of unravelling the molecular pathways involved in cardiac function in normal and pathological states has increased efforts to develop co-adjuvant therapies as pharmacological and interventional options. Gene therapy is emerging as a suitable alternative, with substantial progress in preclinical models of CVD.
Ding et al. The advantages of the AAV vector-based therapeutic strategies over the other available recombinant vectors have positioned this delivery system as the preferred option for many of the gene therapy approaches for HF. However, the ability to obtain sustained expression of the gene of interest may not always be warranted and sometimes transient expression may be preferred based on safety considerations e.
Though Ad vectors may at first glance seem ideally suited to achieve robust yet transient expression of a given therapeutic gene, this short-term expression results from immune complications intrinsic to this type of vectors. This inflammatory risk undermines the safety of adenoviral vector for CVD gene therapy and needs to be carefully assessed, even in the context of loco-regional catheter-mediated vector delivery into the myocardium.
The physiological and structural differences between animal models and humans and the development of immune response against the transgene products, the gene-modified cells, or the vectors themselves pose important challenges for clinical translation. For some gene therapy applications, it would be desirable to be able to control the duration and strength of the expression of the therapeutic gene, using clinically relevant approaches, which are now being developed. Gene therapy clinical trials in ischaemic heart disease yielded limited results compared with preclinical models, with some improvement in secondary endpoints but no improvement in perfusion or myocardial function.
The first clinical trial for HF reported substantial benefits in patients with severe angina, which justified the progression to larger clinical trials. In the future, consensus clinical and functional endpoints as well as the most appropriated measurement methods should be established to allow a clear and comparable understanding of the results between the different clinical trials.
As gene therapy is currently also being used to treat non-lethal diseases in children, the hope is that the majority of patients who suffer from less severe heart disease may ultimately benefit from the advances in gene therapy. We thank the members of the Department of Gene Therapy and Regenerative Medicine and our collaborators for their various contributions to some of the work presented in this review.
Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Gene therapy and CVDs. Therapeutic genes for gene therapy for CVD. Conclusions and future perspectives. Editor's Choice. Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation Melvin Y.
Oxford Academic. Google Scholar. Thierry VandenDriessche. Marinee K. Article history. Revision Received:. PDF Views. Cite Citation. Permissions Icon Permissions. Abstract Gene therapy is a promising modality for the treatment of inherited and acquired cardiovascular diseases. View Large. View large Download slide. Preclinical gene therapy studies for heart failure and other cardiovascular diseases. AC6 2. Table 4. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study.
Search ADS. Intravenous adeno-associated virus serotype 8 encoding urocortin-2 provides sustained augmentation of left ventricular function in mice. Improved function of the failing rat heart by regulated expression of insulin-like growth factor I via intramuscular gene transfer.
Gene therapy for heart disease: molecular targets, vectors and modes of delivery to myocardium. Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery. Ultrasound-targeted gene delivery induces angiogenesis after a myocardial infarction in mice.
Repeated and targeted transfer of angiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair. Enhanced delivery of microRNA mimics to cardiomyocytes using ultrasound responsive microbubbles reverses hypertrophy in an in-vitro model. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Interactions of adenovirus vectors with blood: implications for intravascular gene therapy applications. Helper-dependent adenoviral vector achieves prolonged, stable expression of interleukin in rabbit carotid arteries but does not limit early atherogenesis.
In vivo myocardial gene transfer: optimization, evaluation and direct comparison of gene transfer vectors. Myocardial transfection of hypoxia inducible factor-1alpha via an adenoviral vector during coronary artery bypass grafting. A multicenter phase I and safety study. Immune response to recombinant capsid proteins of adenovirus in humans: antifiber and anti-penton base antibodies have a synergistic effect on neutralizing activity.
Epitopes expressed in different adenovirus capsid proteins induce different levels of epitope-specific immunity. Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Increased regional function and perfusion after intracoronary delivery of adenovirus encoding fibroblast growth factor 4: report of preclinical data.
Adeno-associated virus AAV vectors achieve prolonged transgene expression in mouse myocardium and arteries in vivo: a comparative study with adenovirus vectors. Efficient transduction of primary vascular cells by the rare adenovirus serotype 49 vector. Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Efficacy and safety of adeno-associated viral vectors based on serotype 8 and 9 vs.
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Clades of Adeno-associated viruses are widely disseminated in human tissues. Comparative cardiac gene delivery of adeno-associated virus serotypes 1—9 reveals that AAV6 mediates the most efficient transduction in mouse heart. Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo.
Gene Therapy in Cardiovascular Disease
Di Pasquale. A single direct injection into the left ventricular wall of an adeno-associated virus 9 AAV9 vector expressing extracellular superoxide dismutase from the cardiac troponin-T promoter protects mice against myocardial infarction. Transendocardial delivery of AAV6 results in highly efficient and global cardiac gene transfer in rhesus macaques. Liver-specific transcriptional modules identified by genome-wide in silico analysis enable efficient gene therapy in mice and non-human primates.
Efficient and selective AAV2-mediated gene transfer directed to human vascular endothelial cells. Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors. Vascular bed-targeted in vivo gene delivery using tropism-modified adeno-associated viruses. A single intravenous injection of adeno-associated virus serotype-9 leads to whole body skeletal muscle transduction in dogs. The next step in gene delivery: molecular engineering of adeno-associated virus serotypes.
Heart-targeted adeno-associated viral vectors selected by in vivo biopanning of a random viral display peptide library.