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    • Although the concept of direct interference with

    2018-10-20

    Although the concept of direct interference with the genetic and molecular foundation of cardiac bromodomain inhibitor is simple and elegant, myocardial gene transfer is difficult to achieve as a clinical reality. While the use of certain vectors ensures durable release of VEGF without genome integration, these approaches are limited by low gene transfer efficiency (Hinkel et al., 2011). Improved VEGF165 expression with adenoviral vectors leads to more robust neovascularization; but also contributes to untoward effects, including potential genomic integration, systemic inflammation against the viral vectors (Wright et al., 2001), local edema (Rutanen et al., 2004) or angiomas (Schwarz et al., 2000) as a result of prolonged exposure to VEGF165. These side effects might have masked the therapeutic benefit induced by VEGF165. Therefore, better delivery technologies with more regulated spatial and temporal expression of therapeutic gene products are needed. To address issues associated with non-viral and viral plasmid-mediated gene therapies, we (Zangi et al., 2013; Lui et al., 2013) and others (Kariko et al., 2005, 2011; Kormann et al., 2011; Mandal and Rossi, 2013; Warren et al., 2010) have utilized modified mRNAs (modRNAs) as a non-immunogenic tool to deliver proteins of interest into mammalian cells with high efficiency. Since the immune system has a crucial role in guarding against infections by detecting microbial metabolism, both DNA and RNA can activate dendritic cells of the innate immunity through recognition by Toll-like receptors (TLRs). In translational studies, nucleoside modifications are, therefore, needed to ensure escape from immune surveillance. It has been reported that replacement of cytidine with 5-methyl-cytidine and uridine with pseudouridine suppresses RNA recognition by dendritic cells via TLRs 3, 7 and 8 (Fig. 2) (Kariko et al., 2005). Therefore, incorporation of modRNA both reduces innate immune activation and increases efficiency for mRNA translation (Kariko et al., 2011) (Fig. 2). Recently, it has been demonstrated that twice weekly application with an aerosol containing surfactant protein B (SP-B) in the form of modRNA restored 71% expression of the wildtype SP-B protein in vivo and prolonged survival of mice with a lethal congenital lung disease attributed to SP-B deficiency (Kormann et al., 2011). In addition to the added stability of modRNAs compared to mRNAs, the non-integrating nature of modRNAs also allows transient expression of proteins which, if prolonged, might generate side effects. For instance, high doses of VEGF165 can lead to formation of leaky blood vessels (vascular hyperpermeability) (Nagy et al., 2012) and hypotension (excessive release of nitric oxide) (Yang et al., 2002); therefore, the use of VEGF modRNA could be safer than the use of integrating vectors. The identification of VEGF165 as a cell-fate switch in determining vascular specification of the human Isl1-expressing cardiovascular progenitors has led to pioneering work in using VEGF165 modRNA as a therapeutic paracrine factor for driving heart regeneration (Zangi et al., 2013; Lui et al., 2013). Direct injection of a single paracrine factor such as VEGF165 in the form of modRNAs not only leads to replication and reactivation of the endogenous, quiescent WT1+ adult epicardial cells in the infarcted myocardium, but also directs differentiation of these cells away from a fibroblastic, scar-forming cell fate (Zhou et al., 2008) and toward vascular and myocardial cell fates (Zangi et al., 2013) (Fig. 3). Such an approach stimulates the endogenous regenerative capacity of an infarcted adult heart by limiting pathological remodeling, effecting a significant improvement in heart function including increased ejection fraction, reduced fibrosis and prolonged survival (Zangi et al., 2013). Nevertheless, future studies are still needed to determine whether the modRNA technology is a safer and more efficacious approach compared to other systems previously employed in pre-clinical and clinical studies for delivering paracrine factors and signaling molecules.