CD163 overexpression using a macrophage-directed gene therapy approach improves wound healing in ex vivo and in vivo human skin models

The extracellular matrix glycosaminoglycan hyaluronan plays a key role in the development and pathogenesis of malignant disease. Reflecting its functional importance, the molecule is expressed at greatly elevated levels within many solid tumors. Although little explored, differences in the level of hyaluronan present in normal and malignant tissues could potentially be exploited to more effectively target gene therapy to tumor sites in vivo. As a first step toward this goal, we describe here a family of chimeric proteins in which the extracellular ligand-binding domain of the hyaluronan receptor CD44 is fused in-frame to the cytoplasmic “death domain” of the pro-apoptotic protein Fas. Although these chimeric proteins can be stably expressed on the surface of transduced tumor cells in the absence of hyaluronan, upon interaction with the ligand, apoptosis is rapidly induced. Both exogenous and endogenous tumor produced hyaluronan can function as triggers, dramatically reducing clonogenic potential. Together, these studies help validate a broadly applicable gene therapy approach in which the presence of particular multivalent ligands within the tumor microenvironment can be exploited for therapeutic gain.

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Abstract 258: Pulmonary Overexpression of SERCA2A Improves Electrical Dysfunction and Suppresses Arrhythmias in Monocrotaline-induced Right Ventricular Failure

Circulation Research ◽

10.1161/res.121.suppl_1.258 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Benjamin Strauss ◽

Yassine Sassi ◽

Irene C Turnbull ◽

Carlos Bueno-Beti ◽

Erik Kohlbrenner ◽

...

Keyword(s):

Gene Therapy ◽

Right Ventricular ◽

Ex Vivo ◽

Sprague Dawley ◽

Therapy Approach ◽

Gene Therapy Approach ◽

Sprague Dawley Rats ◽

Complete Reversal ◽

Cardiac Gene ◽

Pulmonary Arterial

Background: Pulmonary Arterial Hypertension (PAH) is a major cause of mortality due, in large part to right ventricular (RV) failure. Its electrophysiological (EP) effects however are poorly defined. Recently, a gene therapy approach targeting SERCA2a (S2A) to the lungs improved RV mechanical function in a rodent PAH model. Whether this approach improves myocardial EP properties remains unknown. Methods: Male Sprague Dawley rats received a subcutaneous injection of monocrotaline (MCT 60mg/kg) leading to PAH induced RV failure. Three wks later, rats underwent intratracheal delivery of aerosolized AAV1.S2A (1E11 gc, N=6) or no treatment (MCT, N=7). Age matched rats served as controls (CTRL, N=5). The EP substrate and risk of VT were assessed using high resolution optical action potential (AP) mapping in ex vivo perfused hearts. Results: MCT (6/7) but not CTRL (0/5) hearts were prone to pacing-induced VT (P<0.01). S2A gene therapy markedly suppressed the incidence of VT to <15% (P<.05 vs MCT). Investigation of the EP substrate revealed complete reversal of slow myocardial conduction in S2A treated compared to untreated MCT rats (Fig A, B) . AP duration (APD) and heterogeneity were increased in MCT and partially reversed by AAV1.S2A. Underlying the rise in heterogeneity was selective APD prolongation on the RV side causing >90 degree clockwise shift in the orientation of the transepicardial gradient, an effect which was not reversed by AAV1.S2A (Fig C arrows) . Conclusion: S2A gene therapy to the lungs ameliorates PAH induced EP remodeling and arrhythmia propensity. Our findings highlight for the first time the utility of a non-cardiac gene therapy approach for arrhythmia suppression.

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