Catheter-based Intramyocardial Injection of FGF1 or NRG1-loaded MPs Improves Cardiac Function in a Preclinical Model of Ischemia-Reperfusion

Abstract

Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials.

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

“…For example, among these 10 classifiers, AGER has been implicated in both HF [61], through extracellular matrix remodeling, and MD development [62], through inflammation, oxidative stress, and basal laminar deposit formation between retinal pigment epithelium cells and the basal membrane; furthermore, this receptor is known to be modulated by AT1R [63], valsartan target. Similarly, FGF1 has been proposed to improve cardiac function after HF [64], as well as to promote choroid neovascularization leading to MD [47]. Moreover, FGF1 is regulated by angiotensin II through ATGR2 [65], another protein suggested as classifier in the current analysis that is known to mediate some of the effects of AT1R antagonists, such as valsartan [41,42].…”

Therapeutic approaches for cardiac regeneration and repair

“…To enhance exposure of the injured heart to the therapeutic growth factors, scaffolds of biomaterials that enable sustained release of the factors to the target sites have been used and have shown improved cardioprotective effects. For instance, in a pig MI model, loading NRG1 and fibroblast growth factor 1 (FGF1) into microparticles provided sustained local release of the therapeutic factors, which improved left ventricular function associated with increased angiogenesis and reduced ventricular remodelling 91 (TABLE 1). Additionally, improved gene- based therapeutics have also led to increased efficiency of delivery and expression of therapeutic factors, such as synthetic modified RNA, a method that has been used to express human VEGFA in the mouse heart after MI 92 .…”

Toward Regeneration of the Heart: Bioengineering Strategies for Immunomodulation

“…As an example, Cohen et al developed a hydroxyethyl methacrylate (HEMA)-based injectable hydrogel system to directly deliver NRG to the myocardial border zone in a rat MI model, and showed augmented cardiomyocyte mitotic activity, decreased apoptosis, and greatly enhanced LV function without off-target exposure (169). Other injectable systems that have been tested for NRG delivery include PLGA-microparticles, which showed increased ejection fraction and also improved angiogenesis when delivered with a percutaneous intramyocardial injection in rat (170) and porcine preclinical models of MI (171).…”