Macrophages are mononuclear phagocytes established during embryogenesis and derived from the yolk sac or the fetal liver but also recruited from the blood and bone marrow under proliferative inflammatory conditions (such as tissue repair). Most importantly, they take on distinct phenotypes and functions crucial to healing upon localization in the wound. The objective of this review is to summarize recent findings in regard to the cellular mechanisms of macrophages and chronic wounds. Advances in the potential use of macrophage therapy have arisen based, in part, on the fact that early recruitment of macrophages is critical to wound healing. Higher quality evidence is needed to support the use of macrophage therapy for chronic wound types, as is a better understanding of the signaling related to macrophage polarization, activation of macrophages, and their effect of mechanisms of repair. An evaluation of the currently available research on mechanism of action may lead to a better understanding of the signaling processes of the many macrophage phenotypes, as well as their roles and outcomes in wound healing, which could then guide the development and eventual widespread use of macrophage therapies.

e14652 Background: Cholangiocarcinoma (CCA) is a hepatobiliary cancer and although there have been advances recently there is a need for additional treatment methods for patients. Over expressions of TGF-β1 and COX-2 have been reported to play key roles in tumorigenesis of CCA. We studied the effect of STP705 on the growth of HuCCT-1 xenograft tumors in nude mice. STP705 is a TGF-β1/COX-2 specific siRNA combination product formulated in Histidine-Lysine co-Polymer nanoparticle delivery system. Methods: HuCCT-1 xenograft tumors were implanted subcutaneously into 24 BALB/c nude female mice (n = 8/group). Group 1 received vehicle control, group 2 (low-dose) received 8µg of STP705, and group 3 (high-dose) received 16µg of STP705. Intratumoral test article administration and tumor volume measurements were conducted twice a week for 3-weeks. Qualitative analysis was performed on H&E, Picrosirius red (PSR) and immunohistochemistry (IHC) stained sections of tumor tissues. Results: High- and low- dose groups of STP705 reported significantly lower mean tumor volume at day 21 (p = 0.005 & p = 0.036, respectively) as compared to control group. High-dose group reported significantly lower tumor volume at days 11 (p = 0.042), 15 (p = 0.003), and 18 (p = 0.007) as compared to the control group. IHC assessment demonstrated that STP705-treated animals had significantly lower (H-score ± SEM) TGF-β1, COX-2, HSP70, Bcl-xL and MMP-9 staining (52±9, 39±4, 178±8, 25±7 & 7±1, respectively) as compared to control animals (94±11, 66±8, 213±7, 59±8 & 11±2, respectively – with p < 0.05). Assessment of Caspase-3 and H&E (necrosis and inflammation) slides reported higher mean score for STP705-treated animals, while PSR staining reported lower fibroplasia for STP705-treated animals as compared to the control animals. Conclusions: The data suggests that STP705-treatment suppresses TGF-β1 and COX-2 expression resulting in inhibition of (i) tumor cell survival, (ii) fibrosis, (iii) promotes apoptosis, and (iv)decreased invasiveness of tumor cells. Overall, STP705 is an innovative siRNA-based treatment that results in significant suppression of tumor growth in a HuCCT-1 xenograft mouse tumor model.

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Background: Hypertriglyceridemia is a critical risk factor for coronary artery disease. Apolipoprotein C-III (APOC3), produced by liver hepatocytes, regulates triglyceride (TG) levels. We studied effect of novel GalNAc-conjugated APOC3 targeting RNAi trigger (STP125G) on APOC3 and TG levels in humanized liver mouse model. Methods: In dose response study, female uPA-SCID mice (n=4 mice/group), group 1 received PBS control, group 2 received 10mg/kg and group 3 received 30mg/kg STP125G, subcutaneously on day 0. Liver biopsies, plasma and serum samples were collected at week 2. In duration response study, male uPA-SCID mice (n=4 mice/group/timepoint), group 1 received PBS control and group 2 received 10mg/kg STP125G, subcutaneously on day 0. Liver biopsies, plasma and serum samples were collected for each group at weeks 2, 4, 8 and 12. Human APOC3 mRNA (qPCR) and protein (ELISA) levels were measured in liver biopsies and plasma samples, respectively. TGs and total cholesterol (TC) levels were measured in serum samples. Results: In dose response study, animals reported significant suppression of mRNA and reduction of plasma protein levels in 10mg/kg (88% and 91%, respectively) and 30mg/kg (92% and 98%, respectively) dose groups as compared to control group ( p <0.001). Animals also reported significant reductions in TGs and TC levels at 10mg/kg (25% and 33%, respectively) and 30mg/kg (43% and 44%, respectively) dose groups as compared to control group ( p <0.05). In duration response study, treated animals reported significant suppression of mRNA levels at week 2 (83%), week 4 (85%) and week 8 (48%) as compared to control group ( p <0.0001). Treated animals reported significant reduction in plasma protein levels at week 2 (82%; p <0.0001), week 4 (89%; p <0.0001) and week 8 (70%; p =0.0005) as compared to control group. At week 4, treated animals reported significant reduction in TGs (53%; p=0.0079) and TC (36%; p=0.0072). Conclusions: The studies demonstrated that a single administration of STP125G, in a humanized liver mouse model, results in significant suppression of human APOC3 mRNA and plasma protein levels that lasts for up to 8 weeks. It also suggests treatment with STP125G results in lowering of triglycerides and total cholesterol in the treated animals.