Papers by Victoria Jurisch
Nature Medicine, 2020
in vitro and in vivo. A.S. generated and analysed dTomato pigs for AAV-Cre transduction. A.M. and... more in vitro and in vivo. A.S. generated and analysed dTomato pigs for AAV-Cre transduction. A.M. and K.-L.L. conceived and supervised the iPSC study and provided financial support. A.B.M., D.S., T.H. and S.S. performed all experiments with iPSCs and their muscle derivatives. B.C. generated, characterized, and differentiated the iPSC lines. A.B.M. generated isogenic hDMDΔ51-52 hiPSCs. D.S., R.D., and T.D. analysed data. T.F. and F.F. performed mass spectrometry. C.M.S., A.D. and D.S. performed the ex-vivo experiments on heart slices and analysed data. S.K. and M.W. provided human patient blood for reprogramming and conceptual advice. C.K. and A.M. wrote the paper. All authors commented on and edited the manuscript. Competing interest C.K. and W.W. have filed a patent for G2-AAV9-Cas9-gE51, which is covered by the results of Figures 1-3. All other authors have no competing interest.
Nature Cell Biology
Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes... more 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. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differenti...
Advanced Science
Background and Objective An orally disintegrating film (ODF) formulation of vitamin D3 that disso... more Background and Objective An orally disintegrating film (ODF) formulation of vitamin D3 that dissolves rapidly in the mouth without drinking or chewing may be a worthwhile alternative to currently available drug products for therapeutic vitamin D supplementation. This study aimed to compare the bioavailability of a single dose of a vitamin D3 25000 I.U. ODF with those of a marketed oral vitamin D3 preparation in healthy subjects. Methods This Phase 1, randomised, parallel-group, open-label study compared the pharmacokinetics of calcifediol [25(OH) D3], the precursor of bioactive vitamin D3, after a single dose of a new vitamin D3 25,000 I.U. ODF with those of a Reference formulation (vitamin D3 25000 I.U./2.5 mL oral solution) in healthy adult subjects using a validated liquid chromatographytandem mass spectrometry (LC-MS/MS) assay. The primary objective was bioavailability under fed conditions, defined as maximum plasma concentration (C max) of 25(OH)D3 and area under the concentration-time curve from time zero to time t, the last quantifiable concentration (AUC 0−t). The pharmacokinetics of 25(OH)D3 were also evaluated following the ODF administration under fasting conditions. Subjects were randomised to receive a single dose of the vitamin D3 25000 I.U. ODF or the Reference oral solution under fed conditions or the vitamin D3 ODF under fasting conditions. Results Forty-eight healthy subjects were randomised and completed the study. Overall, the pharmacokinetic profile was very similar across the three treatment groups, and bioavailability did not significantly differ among treatments. Under fed conditions, mean 25(OH)D3 plasma values for C max were 6.68 ± 2.03 versus 6.61 ± 2.62 ng/mL for the Test versus Reference formulations. Corresponding values for AUC 0−t were 2364.80 ± 1336.97 versus 2150.52 ± 1622.76 ng/mL × h. Mean C max was slightly lower (6.68 ± 2.03 vs 7.23 ± 1.48 ng/mL) and the time to reach peak concentration was delayed (144 h [36-312] versus 42 h (2-480]) with the ODF under fed versus fasting conditions (p = 0.0371). The point estimates and 90 % CIs of the Test fed /Reference fed ratios of the geometric means showed that the bioavailability of exogenous 25(OH)D3 was, both in rate and extent of absorption, slightly higher with the vitamin D3 ODF than the vitamin D3 oral solution under the administration conditions recommended for the vitamin D3 oral solution. Palatability and ease of use of the ODF were satisfactory. Conclusion The new ODF 25000 I.U. formulation provided a valuable alternative to the marketed oral solution for therapeutic vitamin D supplementation, with a bioavailability that was slightly higher than that of the vitamin D3 oral solution administered under the same conditions. Trial Registration The study was retrospectively registered with the ISRCTN Registry (Registry code: ISRCTN13208948) on
AntimiR-132 Attenuates Myocardial Hypertrophy in an Animal Model of Percutaneous Aortic Constriction
Journal of the American College of Cardiology, 2021
BACKGROUND Pathological cardiac hypertrophy is a result of afterload-increasing pathologies inclu... more BACKGROUND Pathological cardiac hypertrophy is a result of afterload-increasing pathologies including untreated hypertension and aortic stenosis. It features progressive adverse cardiac remodeling, myocardial dysfunction, capillary rarefaction, and interstitial fibrosis often leading to heart failure. OBJECTIVES This study aimed to establish a novel porcine model of pressure-overload-induced heart failure and to determine the effect of inhibition of microribonucleic acid 132 (miR-132) on heart failure development in this model. METHODS This study developed a novel porcine model of percutaneous aortic constriction by implantation of a percutaneous reduction stent in the thoracic aorta, inducing progressive remodeling at day 56 (d56) after pressure-overload induction. In this study, an antisense oligonucleotide specifically inhibiting miR-132 (antimiR-132), was regionally applied via intracoronary injection at d0 (percutaneous transverse aortic constriction induction) and d28. RESULTS...
bioRxiv, 2020
Human heart regeneration is one of the most critical unmet clinical needs at a global level1. Mus... more Human heart regeneration is one of the most critical unmet clinical needs at a global level1. Muscular regeneration is hampered both by the limited renewing capacity of adult cardiomyocytes2-4 and the onset of cardiac fibrosis5,6, resulting in reduced compliance of the tissue. Primate have proven to be ideal models for pluripotent stem cell strategies for heart regeneration, but unravelling specific approaches to drive cell migration to the site of injury and inhibition of subsequent fibrosis have been elusive. Herein, by combining human cardiac progenitor lineage tracing and single-cell transcriptomics in injured non-human primate heart bio-mimics, we uncover the coordinated muscular regeneration of the primate heart via directed migration of human ventricular progenitors to sites of injury, subsequent fibroblast repulsion targeting fibrosis, and ultimate functional replacement of damaged cardiac muscle by differentiation and electromechanical integration. Single-cell RNAseq captur...
Atherosclerosis and associated ischemic organ dysfunction represent the number one cause of morta... more Atherosclerosis and associated ischemic organ dysfunction represent the number one cause of mortality worldwide. While the key drivers of atherosclerosis, arterial hypertension, hypercholesterolemia and diabetes mellitus, are well known disease entities and their contribution to the formation of atherosclerotic plaques are intensively studied and well understood, less effort is put on the effect of these disease states on microvascular structure an integrity. In this review we summarize the pathological changes occurring in the vascular system in response to prolonged exposure to these major risk factors, with a particular focus on the differences between these pathological alterations of the vessel wall in larger arteries as compared to the microcirculation. Furthermore, we intend to highlight potential therapeutic strategies to improve microvascular function during atherosclerotic vessel disease.
Ischemic heart diseases are classified among the leading cause of death and reduced life quality ... more Ischemic heart diseases are classified among the leading cause of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop chronic heart failure over time. We have recently reported that a fragment of the extra cellular matrix (ECM) protein Agrin promotes cardiac regeneration following MI in adult mice. Here, we tested the therapeutic potential of Agrin in a preclinical porcine model, comprising either 3 or 28 days (d) reperfusion period. We first demonstrate that local (antegrade) delivery of recombinant human Agrin (rhAgrin) to the infarcted pig heart can target the affected regions in an efficient and clinically-relevant manner. Single dose of rhAgrin resulted in significant improvement in heart function, infarct size, fibrosis and adverse remodeling parameters 28 days post MI. Short-term MI experiment along with complementary murine MI studies...
Supplemental Digital Content is available in the text. Background: Ischemic heart diseases are le... more Supplemental Digital Content is available in the text. Background: Ischemic heart diseases are leading causes of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a large number of patients with MI develop chronic heart failure over time. We previously reported that a fragment of the extracellular matrix protein agrin promotes cardiac regeneration after MI in adult mice. Methods: To test the therapeutic potential of agrin in a preclinical porcine model, we performed ischemia–reperfusion injuries using balloon occlusion for 60 minutes followed by a 3-, 7-, or 28-day reperfusion period. Results: We demonstrated that local (antegrade) delivery of recombinant human agrin to the infarcted pig heart can target the affected regions in an efficient and clinically relevant manner. A single dose of recombinant human agrin improved heart function, infarct size, fibrosis, and adverse remodeling ...
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Papers by Victoria Jurisch