The Combination of Vascular Endothelial Growth Factor A (VEGF-A) and Fibroblast Growth Factor 1 (FGF1) Modified mRNA Improves Wound Healing in Diabetic Mice: An Ex Vivo and In Vivo Investigation.

Background: Diabetic foot ulcers (DFU) pose a significant health risk in diabetic patients, with insufficient revascularization during wound healing being the primary cause. This study aimed to assess microvessel sprouting and wound healing capabilities using vascular endothelial growth factor (VEGF-A) and a modified fibroblast growth factor (FGF1).

Methods: An ex vivo aortic ring rodent model and an in vivo wound healing model in diabetic mice were employed to evaluate the microvessel sprouting and wound healing capabilities of VEGF-A and a modified FGF1 both as monotherapies and in combination.

Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting.

Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.

Selecting the right therapeutic target for kidney disease.

Kidney disease is a complex disease with several different etiologies and underlying associated pathophysiology. This is reflected by the lack of effective treatment therapies in chronic kidney disease (CKD) that stop disease progression. However, novel strategies, recent scientific breakthroughs, and technological advances have revealed new possibilities for finding novel disease drivers in CKD.

Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure.

The dysregulated physical interaction between two intracellular membrane proteins, the sarco/endoplasmic reticulum Ca ATPase and its reversible inhibitor phospholamban, induces heart failure by inhibiting calcium cycling. While phospholamban is a bona-fide therapeutic target, approaches to selectively inhibit this protein remain elusive. Here, we report the in vivo application of intracellular acting antibodies (intrabodies), derived from the variable domain of camelid heavy-chain antibodies, to modulate the function of phospholamban.

Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors.

Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host-graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair.

Citrate-Saline-Formulated mRNA Delivery into the Heart Muscle with an Electromechanical Mapping and Injection Catheter Does Not Lead to Therapeutic Effects in a Porcine Chronic Myocardial Ischemia Model.

Based on recent success in using modified RNA in clinical applications, we tested the safety, feasibility, and efficacy of direct delivery of citrate-saline-formulated mRNA into an hibernating ischemic heart muscle using an electromechanical mapping and injection catheter system (NOGA/Myostar) in a porcine chronic myocardial ischemia model. Chronic ischemia was induced in domestic pigs ( = 24) using a bottleneck stent placed in the left anterior descending coronary artery. Low (1 mg) and high (7.

Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy.

Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca handling is a key feature of HF pathophysiology. Restoring the Ca regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies.

Mathematical Model Predicts that Acceleration of Diabetic Wound Healing is Dependent on Spatial Distribution of VEGF-A mRNA (AZD8601).

Introduction: Pharmacologic approaches for promoting angiogenesis have been utilized to accelerate healing of chronic wounds in diabetic patients with varying degrees of success. We hypothesize that the distribution of proangiogenic drugs in the wound area critically impacts the rate of closure of diabetic wounds. To evaluate this hypothesis, we developed a mathematical model that predicts how spatial distribution of VEGF-A produced by delivery of a modified mRNA (AZD8601) accelerates diabetic wound healing.

Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes.

Aims: Hypertrophic cardiomyopathy (HCM) is characterized by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM.

BMP-2 and VEGF-A modRNAs in collagen scaffold synergistically drive bone repair through osteogenic and angiogenic pathways.

Bone has a remarkable potential for self-healing and repair, yet several injury types are non-healing even after surgical or non-surgical treatment. Regenerative therapies that induce bone repair or improve the rate of recovery are being intensely investigated. Here, we probed the potential of bone marrow stem cells (BMSCs) engineered with chemically modified mRNAs (modRNA) encoding the hBMP-2 and VEGF-A gene to therapeutically heal bone.

Model-Based Analysis Reveals a Sustained and Dose-Dependent Acceleration of Wound Healing by VEGF-A mRNA (AZD8601).

Intradermal delivery of AZD8601, an mRNA designed to produce vascular endothelial growth factor A (VEGF-A), has previously been shown to accelerate cutaneous wound healing in a murine diabetic model. Here, we develop population pharmacokinetic and pharmacodynamic models aiming to quantify the effect of AZD8601 injections on the dynamics of wound healing. A dataset of 584 open wound area measurements from 131 mice was integrated from 3 independent studies encompassing different doses, dosing timepoints, and number of doses.

Ticagrelor Enhances Release of Anti-Hypoxic Cardiac Progenitor Cell-Derived Exosomes Through Increasing Cell Proliferation In Vitro.

Despite the widespread clinical use of cardioprotection by long-term direct antagonism of P2Y12 receptor, underlying mechanisms are unclear. Here, we identify how release of pro-survival exosomes from human cardiac-derived mesenchymal progenitor cells (hCPCs) is regulated by clinically relevant dose of ticagrelor (1 μM), an oral selective and reversible non-thienopyridine P2Y inhibitor. Ticagrelor-induced enhancement of exosome levels is related to increased mitotic activity of hCPCs.

In vivo imaging of hemodynamic redistribution and arteriogenesis across microvascular network.

Objective: Arteriogenesis is an important mechanism that contributes to restoration of oxygen supply in chronically ischemic tissues, but remains incompletely understood due to technical limitations. This study presents a novel approach for comprehensive assessment of the remodeling pattern in a complex microvascular network containing multiple collateral microvessels.

Methods: We have developed a hardware-software integrated platform for quantitative, longitudinal, and label-free imaging of network-wide hemodynamic changes and arteriogenesis at the single-vessel level.

Cell-mediated delivery of VEGF modified mRNA enhances blood vessel regeneration and ameliorates murine critical limb ischemia.

Synthetic chemically modified mRNAs (modRNA) encoding vascular endothelial growth factor (VEGF) represents an alternative to gene therapy for the treatment of ischemic cardiovascular injuries. However, novel delivery approaches of modRNA are needed to improve therapeutic efficacy in the diseased setting. We hypothesized that cell-mediated modRNA delivery may enhance the in vivo expression kinetics of VEGF protein thus promoting more potent angiogenic effects.

Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes.

Chemically modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. We report a first-time-in-human study of this modality, aiming to evaluate safety and potential therapeutic effects. Men with type 2 diabetes mellitus (T2DM) received intradermal injections of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) or buffered saline placebo (ethical obligations precluded use of a non-translatable mRNA control) at randomized sites on the forearm.

Regenerating the field of cardiovascular cell therapy.

The retraction of >30 falsified studies by Anversa et al. has had a disheartening impact on the cardiac cell therapeutics field. The premise of heart muscle regeneration by the transdifferentiation of bone marrow cells or putative adult resident cardiac progenitors has been largely disproven.

Rapid Production of Human VEGF-A following Intradermal Injection of Modified VEGF-A mRNA Demonstrated by Cutaneous Microdialysis in the Rabbit and Pig .

Chemically modified mRNA is a novel, highly efficient, biocompatible modality for therapeutic protein expression that may overcome the challenges and safety concerns with current gene therapy strategies. We explored the efficiency of intradermally injected modified VEGF-A mRNA (VEGF-A mRNA) formulated in a biocompatible citrate/saline buffer to locally produce human VEGF-A protein. Rabbits (n=4) and minipigs (n=3) were implanted with subcutaneous microdialysis probes close to the injection sites and interstitial-fluid samples and skin biopsies were analysed for production of VEGF-A protein over time for up to 8 hours.

Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing.

Capable of mediating efficient transfection and protein production without eliciting innate immune responses, chemically modified mRNA holds great potential to produce paracrine factors at a physiologically beneficial level, in a spatiotemporally controlled manner, and with low toxicity. Although highly promising in cardiovascular medicine and wound healing, effects of this emerging therapeutic on the microvasculature and its bioactivity in disease settings remain poorly understood. Here, we longitudinally and comprehensively characterize microvascular responses to AZD8601, a modified mRNA encoding vascular endothelial growth factor A (VEGF-A), in vivo.

Fatty acid metabolism driven mitochondrial bioenergetics promotes advanced developmental phenotypes in human induced pluripotent stem cell derived cardiomyocytes.

Background: Preferential utilization of fatty acids for ATP production represents an advanced metabolic phenotype in developing cardiomyocytes. We investigated whether this phenotype could be attained in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) and assessed its influence on mitochondrial morphology, bioenergetics, respiratory capacity and ultra-structural architecture.

Methods And Results: Whole-cell proteome analysis of day 14 and day 30-CMs maintained in glucose media revealed a positive influence of extended culture on mitochondria-related processes that primed the day 30-CMs for fatty acid metabolism.

Biocompatible, Purified mRNA Improves Cardiac Function after Intracardiac Injection 1 Week Post-myocardial Infarction in Swine.

mRNA can direct dose-dependent protein expression in cardiac muscle without genome integration, but to date has not been shown to improve cardiac function in a safe, clinically applicable way. Herein, we report that a purified and optimized mRNA in a biocompatible citrate-saline formulation is tissue specific, long acting, and does not stimulate an immune response. In small- and large-animal, permanent occlusion myocardial infarction models, mRNA improves systolic ventricular function and limits myocardial damage.

Association of Cardiomyopathy With MYBPC3 D389V and MYBPC3Δ25bpIntronic Deletion in South Asian Descendants.

Importance: The genetic variant MYBPC3Δ25bp occurs in 4% of South Asian descendants, with an estimated 100 million carriers worldwide. MYBPC3 Δ25bp has been linked to cardiomyopathy and heart failure. However, the high prevalence of MYBPC3Δ25bp suggests that other stressors act in concert with MYBPC3Δ25bp.

Insulin resistance, endothelial function, angiogenic factors and clinical outcome in non-diabetic patients with chest pain without myocardial perfusion defects.

Background: Patients with angina-like symptoms without myocardial perfusion scintigram (MPS)-verified abnormality may still be at risk for cardiovascular events. We hypothesized that insulin resistance could play a role in this population even without diagnosed diabetes. We further explored physiological and blood biomarkers, as well as global gene expression patterns that could be closely related to impaired glucose homeostasis to deepen our mechanistic understanding.