Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).
Rationale: Elevated plasma triglyceride levels have been recognized as a risk factor for the development of coronary heart disease. Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma triglyceride concentrations. Furthermore, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. To date, no selective apoC-III therapeutic agent has been evaluated in the clinic. Objective: To test the hypothesis that selective inhibition of apoC-III with antisense drugs in preclinical models and in healthy volunteers would reduce plasma apoC-III and triglyceride levels. Methods and Results: Rodent- and human-specific second-generation antisense oligonucleotides were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice, and nonhuman primates. We demonstrated the selective reduction of both apoC-III and triglyceride in all preclinical pharmacological evaluations. We also showed that inhibition of apoC-III was well tolerated and not associated with increased liver triglyceride deposition or hepatotoxicity. A double-blind, placebo-controlled, phase I clinical study was performed in healthy subjects. Administration of the human apoC-III antisense drug resulted in dose-dependent reductions in plasma apoC-III, concomitant lowering of triglyceride levels, and produced no clinically meaningful signals in the safety evaluations. Conclusions: Antisense inhibition of apoC-III in preclinical models and in a phase I clinical trial with healthy subjects produced potent, selective reductions in plasma apoC-III and triglyceride, 2 known risk factors for cardiovascular disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.
Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA), a transmissible lung cancer in sheep (14). JSRV induces tumors rapidly under experimental conditions (28), and we previously showed that the JSRV envelope protein functions as an oncogene, in that it can morphologically transform mouse NIH 3T3 and rat Rat 208F fibroblasts in vitro (24, 34). The mechanism(s) by which JSRV Env can cause cell transformation is of great interest. We also previously showed that the cytoplasmic tail of the envelope transmembrane (TM) protein is necessary for fibroblast transformation (29). In particular, a putative docking site for phosphatidylinositol 3-kinase (PI3K) in the cytoplasmic tail was implicated, because mutations in this motif (YXXM) eliminated transformation. On the other hand, we subsequently found that disabling PI3K signaling in cells does not prevent JSRV transformation, although in such cells the downstream effector molecule Akt/protein kinase B (PKB) was still phosphorylated (25). Also, Akt is not absolutely required for JSRV transformation of chicken embryo fibroblasts (40). Thus, the role of the PI3K-Akt pathway in JSRV transformation is unclear, although downstream parts of the pathway in particular might be involved.Akt is known to phosphorylate several downstream substrates that are involved in several signaling pathways associated with human cancers (5). Phosphorylation substrates of Akt include glycogen synthase kinase 3 (GSK-3), the Forkhead transcription factor, the proapoptotic Bad protein, and the mammalian target of rapamycin (mTOR). Akt phosphorylation of GSK-3, Forkhead, and Bad inactivates these proteins, while phosphorylation of mTOR activates it. In particular, the mammalian target of rapamycin (mTOR) [SEP]) is a 289-kDa serine/threonine kinase that is an ortholog of the Saccharomyces cerevisiae target of rapamycin 1 (TOR1) and TOR2 (8,35). mTOR is a key regulator of cell growth and division at the level of translation (17) by activating (phosphorylating) p70 S6 kinase and phosphorylating (inactivating) 4EBP1, a negative regulatory binding protein of translation initiation factor eIF4G (32). The mTOR inhibitor rapamycin was first identified as an antifungal agent (36, 37). Its specificity
Dysregulated mRNA translation is implicated in the pathogenesis of many human cancers including chronic myelogenous leukemia (CML). Because our prior work has specifically implicated translation initiation in CML, we tested compounds that could modulate translation initiation and polysomal mRNA assembly. Here, we evaluated the activity of one such compound, CGP57380, against CML cells and explored its mechanisms of action. First, using polysomal mRNA profiles, we found that imatinib and CGP57380 could independently, and cooperatively, impair polysomal mRNA loading. Imatinib and CGP57380 also synergistically inhibited the growth of Ba/F3-Bcr-Abl and K562 cells via impaired cell cycle entry and increased apoptosis. Mechanistically, CGP57380 inhibited efficient polysomal assembly via two processes. First, it enhanced imatinib-mediated inhibition of eukaryotic initiation factor 4F induction, and second, it independently impaired phosphorylation of ribosomal protein S6 on the preinitiation complex. We also identified multiple substrates of the mTOR, Rsk, and Mnk kinases as targets of CGP57380. Finally, we found a novel negative-feedback loop to the mitogenactivated protein kinase/Mnk pathway that is triggered by CGP57380 and demonstrated that an interruption of the loop further increased the activity of the combination against imatinib-sensitive and -resistant CML cells. Together, this work supports the inhibition of translation initiation as a therapeutic strategy for treating cancers fueled by dysregulated translation.
This study documents the first specific therapy, to our knowledge, for lowering apo(a)/Lp(a) levels and their associated OxPL. A more potent effect was documented in mice expressing apo(a) with multiple KIV-2 repeats. Targeting liver expression of apo(a) with ASOs directed to KIV-2 repeats may provide an effective approach to lower elevated Lp(a) levels in humans.
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