169 First-in-human safety and mechanism of action (MOA) analyses of repeatedly dosed in vivo gene delivery for directed human type III collagen (COL3) expression in aesthetics

Cardiac fibroblast (CF) proliferation and differentiation into hypersecretory myofibroblasts can lead to excessive extracellular matrix (ECM) production and cardiac fibrosis. In turn, the ECM produced can potentially activate CFs via distinct feedback mechanisms. To assess how specific ECM components influence CF activation, isolated CFs were plated on specific collagen substrates (type I, III, and VI collagens) before functional assays were carried out. The type VI collagen substrate potently induced myofibroblast differentiation but had little effect on CF proliferation. Conversely, the type I and III collagen substrates did not affect differentiation but caused significant induction of proliferation (type I, 240.7 ± 10.3%, and type III, 271.7 ± 21.8% of basal). Type I collagen activated ERK1/2, whereas type III collagen did not. Treatment of CFs with angiotensin II, a potent mitogen of CFs, enhanced the growth observed on types I and III collagen but not on the type VI collagen substrate. Using an in vivo model of myocardial infarction (MI), we measured changes in type VI collagen expression and myofibroblast differentiation after post-MI remodeling. Concurrent elevations in type VI collagen and myofibroblast content were evident in the infarcted myocardium 20-wk post-MI. Overall, types I and III collagen stimulate CF proliferation, whereas type VI collagen plays a potentially novel role in cardiac remodeling through facilitation of myofibroblast differentiation.

Download Full-text

Polyelectrolyte Complexes of Low Molecular Weight PEI and Citric Acid as Efficient and Nontoxic Vectors for in Vitro and in Vivo Gene Delivery

Bioconjugate Chemistry ◽

10.1021/acs.bioconjchem.5b00576 ◽

2016 ◽

Vol 27 (3) ◽

pp. 549-561 ◽

Cited By ~ 27

Author(s):

M. Dolores Giron-Gonzalez ◽

Rafael Salto-Gonzalez ◽

F. Javier Lopez-Jaramillo ◽

Alfonso Salinas-Castillo ◽

Ana Belen Jodar-Reyes ◽

...

Keyword(s):

Molecular Weight ◽

Citric Acid ◽

Gene Delivery ◽

Low Molecular Weight ◽

Polyelectrolyte Complexes ◽

In Vivo Gene Delivery

Download Full-text

In Vivo Gene Delivery into hCD34+ Cells in a Humanized Mouse Model

Methods in Molecular Biology - Viral Vectors for Gene Therapy ◽

10.1007/978-1-61779-095-9_15 ◽

2011 ◽

pp. 367-390 ◽

Cited By ~ 12

Author(s):

Cecilia Frecha ◽

Floriane Fusil ◽

François-Loïc Cosset ◽

Els Verhoeyen

Keyword(s):

Gene Delivery ◽

Mouse Model ◽

Humanized Mouse ◽

Humanized Mouse Model ◽

In Vivo Gene Delivery

Download Full-text

Abstract 39: Adrenal ßArrestin1 Raises Serum Aldosterone Levels And Blood Pressure, Both Significant Stroke Risk Factors, In Experimental Rats And Mice

Stroke ◽

10.1161/str.44.suppl_1.a39 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Anastasios Lymperopoulos ◽

Ashley Bathgate ◽

Norma C Salazar

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Gene Delivery ◽

Adrenal Cortex ◽

Stroke Risk ◽

Fluorescent Protein ◽

Serum Aldosterone ◽

Increased Risk ◽

In Vivo Gene Delivery

Introduction: It is widely accepted nowadays that elevation of serum levels of aldosterone, a mineralocorticoid hormone with toxic effects in several cardiovascular tissues, including the heart and cerebral blood vessels, can significantly raise stroke risk. The success of mineralocorticoid receptor blockers, such as eplerenone, at preventing stroke attacks attests to this. Aldosterone is normally produced and secreted by the adrenal cortex in response to angiotensin II. We recently reported that adrenal βarrestin1 (βarr1) plays a crucial role in the physiological angiotensin II-stimulated aldosterone production in the adrenal cortex, leading to marked elevation of circulating serum aldosterone levels in vivo (Lymperopoulos A. et al., Proc. Natl. Acad. Sci. USA. 2009;106:5825-5830). Hypothesis: Herein, we examined the potential impact of this adrenal βarr1-dependent aldosterone elevation on stroke risk in experimental animals in vivo. Methods: We used the βarr1 knockout (βarr1KO) mouse model, studying it alongside wild type (WT) control mice, and also adult male Sprague-Dawley rats, in which adrenal βarr1 was overexpressed in vivo via adrenal-targeted adenoviral-mediated βarr1 gene transfer. Serum aldosterone was measured by ELISA and blood pressure via telemetry. Results: Serum aldosterone at 7 days post-in vivo gene delivery was markedly elevated in adrenal βarr1-overexpressing rats (536+50 pg/ml), compared to control rats receiving the green fluorescent protein (GFP) adenoviral transgene (235+40 pg/ml, p<0.05, n=5). This translated to a significant increase in mean arterial pressure of the βarr1-overexpressing rats (155+5 mmHg) compared to control GFP-expressing rats (137+8 mmHg, p<0.05, n=5), again at 7 days post-in vivo gene delivery, which was prevented by concurrent eplerenone treatment. In contrast, βarr1KO mice had significantly lower serum aldosterone levels (270+20 pg/ml) compared to WT controls (498+35 pg/ml, p<0.05, n=5), at 4 weeks post-experimental myocardial infarction. Conclusions: Adrenal βarr1 up-regulation can dramatically increase circulating aldosterone levels and systemic blood pressure, thus conferring increased risk for stroke in experimental rodents.

Download Full-text