In the study by Wang et al siRNA

In the study by Wang et al., siRNA knockdown of renalase in the kidney abolished the RPC effect. This would at first glance appear attributable to decreased intracellular renalase, as this is where the siRNA works, but it is also possible that siRNA knockdown significantly decreased extracellular renalase levels and interrupted local paracrine or autocrine loops. Further, the kidney is a major source of circulating renalase, and it is possible siRNA knockdown of renalase e1 activating enzyme in the kidney led to a significant decrease in circulating renalase, although serum renalase levels were not reported. Interestingly, this group has previously reported that administration of recombinant renalase also protects against CIN, and it has been shown in other models of renal injury that recombinant renalase and the renalase-derived peptides are both highly protective, all supporting a crucial role of extracellular renalase-mediated signal transduction in renal protection following insult (). However, this effect is attenuated in renalase deficient mice, suggesting an important role of intracellular renalase in mediating the ultimate cytoprotective effects of extracellular renalase.

Breaking Through the Oncolytic Virus Glass Ceiling There is a great deal of intellectual appeal in the concept of oncolytic viruses (OVs) as programmable biological machines that target, replicate in and ultimately destroy cancer cells. OVs have been under development in academic laboratories around the world for in excess of 20years but like any new therapeutic idea, OVs have faced an uphill battle in achieving clinical validation and ultimately commercial acceptance. Only recently has the herpes virus based therapeutic, Imlygic (talimogene laherparepvec, Amgen), broken through the “glass ceiling” and emerged as an FDA and EMEA approved treatment for advanced melanoma. This has led to a virtual stampede (by OV standards) of small biotechnology companies vying to produce the next “Imylgic”, at last count in excess of twenty burgeoning companies. According to BioCentury (Cuickner-Meisner, 2016) there currently are two OVs in phase III trials, nine in phase II, at least eight in phase I development and the number will increase by the end of the year.
Oncolytic Viruses Have Arrived: But What Are They? What Do They Do? OVs are multi-mechanistic therapeutics but their versatility has left them suffering from an identity crisis - are they in situ vaccines, systemically administered cancer killers, potent oncolytic vaccines, anti-vascular agents, gene therapy vectors, or loco-regional adjuvants that stimulate innate immune reactions? The reality is OVs can be any or all of these things depending upon the virus platform under consideration and the clinical indication (Leveille et al., 2011; Breitbach et al., 2013; Melcher et al., 2011; Russell et al., 2012; Kelly and Russell, 2007; Russell et al., 2014; Kirn and Thorne, 2009; Kaufman et al., 2015; Lichty et al., 2014). With our advanced understanding of the molecular biology of cancers and virus:host interactions we are positioned to rapidly create tailored therapeutics with multiple mechanisms of action. Let\'s first consider OVs as loco-regional in situ vaccines.
Imlygic: The Case for an Oncolytic Virus In Situ Vaccine Since the insightful development of Coley\'s toxin over a century ago, there have been numerous strategies developed to stimulate a cancer patient\'s immune response against their own tumour (Pierce et al., 2015; van der Burg et al., 2016). Much like Coley\'s toxin, these strategies provided provocative responses in small trials of select patients but for the most part, failed when tested more widely. These “adjuvant and vaccine” therapies were designed to drive immune responses against so-called tumour antigens including cancer testis antigens, over-expressed tissue specific proteins, aberrant post-translational modifications and neoepitopes created during malignant evolution (Rosenberg et al., 2004). The reasons for these frustrating failures were revealed by fundamental research into the signaling pathways that regulate our immune systems. We are genetically programmed to rapidly mount immune responses to invading pathogens but at the same time, just as quickly dampen immune responses to avoid acute cytokine storm toxicity and auto-immunity. These homeostatic mechanisms are controlled in large part by integrated immune checkpoint networks and in the tumour microenvironment, these critical regulatory pathways are usurped providing malignant cells with an immunosuppressive cloak (Pardoll, 2012). Given that therapeutics have now been approved that block this negative feedback loop, there is a renewed interest in in situ vaccines and other approaches that may show enhanced activity upon combination with immune checkpoint inhibitors (ICIs). For instance, so-called “viral mimetics” like imiquimod (Vasilakos and Tomai, 2013) and “sting agonists” are in development (Deng et al., 2014; Fu et al., 2015; Wang et al., 2016) in an attempt to re-polarize the tumour microenvironment making it immunologically responsive and like Coley\'s toxin, facilitating an environment conducive to creating an in situ vaccine.