MicroRNAs in cancer: biomarkers, functions and therapy.

Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications.

The molecular and physical information coded within the extracellular milieu is informing the development of a new generation of biomaterials for tissue engineering. Several powerful extracellular influences have already found their way into cell-instructive scaffolds, while others remain largely unexplored. Yet for commercial success tissue engineering products must be not only efficacious but also cost-effective, introducing a potential dichotomy between the need for sophistication and ease of production. This is spurring interest in recreating extracellular influences in simplified forms, from the reduction of biopolymers into short functional domains, to the use of basic chemistries to manipulate cell fate. In the future these exciting developments are likely to help reconcile the clinical and commercial pressures on tissue engineering.

Complexity in biomaterials for tissue engineering

Advances in RNA-sequencing techniques have led to the discovery of thousands of non-coding transcripts with unknown function. There are several types of non-coding linear RNAs such as microRNAs (miRNA) and long non-coding RNAs (lncRNA), as well as circular RNAs (circRNA) consisting of a closed continuous loop. This review guides the reader through important aspects of non-coding RNA biology. This includes their biogenesis, mode of actions, physiological function, as well as their role in the disease context (such as in cancer or the cardiovascular system). We specifically focus on non-coding RNAs as potential therapeutic targets and diagnostic biomarkers.

/pdf/non-coding-rnas-in-development-and-disease-background-57ddx2n5hi.pdf

Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches

Nanoparticle/microparticle-based drug delivery systems for systemic (i.e., intravenous) applications have significant advantages over their nonformulated and free drug counterparts. For example, nanoparticle systems are capable of delivering therapeutics and treating areas of the body that other delivery systems cannot reach. As such, nanoparticle drug delivery and imaging systems are one of the most investigated systems in preclinical and clinical settings. Here, we will highlight the diversity of nanoparticle types, the key advantages these systems have over their free drug counterparts, and discuss their overall potential in influencing clinical care. In particular, we will focus on current clinical trials for nanoparticle formulations that have yet to be clinically approved. Additional emphasis will be on clinically approved nanoparticle systems, both for their currently approved indications and their use in active clinical trials. Finally, we will discuss many of the often overlooked biological, technological, and study design challenges that impact the clinical success of nanoparticle delivery systems.

https://aiche.onlinelibrary.wiley.com/doi/pdf/10.1002/btm2.10003

Nanoparticles in the clinic.

577 from Marina Biotech of Bothell, Washington. Liposomes naturally accumulate in the liver, making liver cancer a logical first indication for MRX34. Because Smarticles (which comprise different mixtures of palmitoyl oleoyl phosphatidyl choline, dioleoyloxytrimethylammonium propane, 1,2-dimyristoylglycerol3-hemisuccinate and cholesterol) are anionic at normal body pH but cationic at lower pH, uptake into tumors—which tend to have lower pH—is enhanced and unwanted interactions with healthy cells prevented, a finding that was borne out in preclinical studies. MRX34 restores the tumor suppressor pathway to normal, inducing apoptosis in tumor cells in vitro and in mouse models of cancer. Studies also show that at the anticipated therapeutic doses, no changes in cytokine profiles are apparent. But others in the field have raised concerns about Mirna’s “replacement” strategy. William Marshall, president and CEO of Boulder, Colorado–based miRagen’s Therapeutics, noted that introducing miRNA into a cell type that wouldn’t normally express that miRNA could result in off-target side effects. “With a microRNA replacement therapy, I would want a microRNA that is broadly expressed in many tissues and is downregulated only in diseased cells. I think that is true for miR-34,” says Marshall. Lammers says he is unaware of any research showing that miR34 is absent in any type of cell in the body. Another general safety concern with miRNA mimics is dosing. “We don’t yet fully understand the pharmacokinetics of microRNA, that is, we don’t know exactly what will happen when you increase cellular levels by 10-fold versus 100-fold versus 1,000-fold,” according to Serge Patrick Nana-Sinkam, a practicing pulmonologist and associate professor of internal medicine at The James Comprehensive Cancer Center of The Ohio State University in Columbus. He adds, “A higher dosage level might actually cause an opposite effect.” Mirna will not know the magnitude of increase in miR-34 cellular levels required for efficacy in humans until biopsy material from patients in clinical trials becomes available. Lammers says healthy liver cells normally have about 300 copies of miR-34, whereas there are only about 100 copies in a liver cancer cell. “I don’t think we have to bring it back to 300 copies per cell because there seems to be a threshold system at work here above which the tumor suppression system will turn back on,” he says, adding that having access to and performing analyses of tumor biopsies could help determine if such a threshold phenomenon truly is in play. Aaron Bouchie Ithaca, NY First microRNA mimic enters clinic

/pdf/first-microrna-mimic-enters-clinic-36gna0mclr.pdf

First microRNA mimic enters clinic

Tissue engineering firms go under

volume 30 number 12 DeCember 2012 nature biotechnology A gene expression test that can help predict which patients need costly and invasive cardiac screening has netted approval for coverage from Medicare’s benefits administrator Palmetto. The Corus CAD gene signature test was developed by CardioDx and first launched in 2009. “This is positive for the company and has implications for other personalized medicine companies,” says Randy Goodman, director of pricing and reimbursement practice at Cambridge, Massachusetts–based Scientia Advisors. The test uses real-time PCR to measure RNA levels of 23 genes to help primary care clinicians and cardiologists determine which nondiabetic patients with uncomplicated chest pain (that is, stable angina) need further screening for coronary artery disease. The gene signature reflects biological changes “driven by inflammation,” says CardioDx president and CEO David Levison. Generating the data to get that coverage “wasn’t easy,” says Levison. While it is relatively straightforward to get such tests to market, “It takes a while to generate the clinical data that payors want. Validation is expensive and time consuming, which explains why there are so few tests on the market,” he says. CardioDx carried out two prospective, multicenter trials to validate the test and is now doing two registry trials. The next challenge for CardioDx will be to broaden its adoption. Physicians tend to automatically send patients for cardiac catheterization if there is a possibility of obstructive heart disease. Relying on a blood test, when they can get a look at the actual arteries, will require convincing. But cost-containment efforts may help the company’s cause. More than half of patients with stable angina, who have costly additional testing, have no observable obstructive coronary disease. CardioDx bet that payors would be interested in identifying who those patients are, and this decision to provide Medicare coverage suggests they have made a convincing argument. Palmetto’s decision to reimburse the Corus CAD test may convince private payors to follow suit. “For payors, this is an issue about evidence,” says Goodman. “Overall, payors are increasingly looking for strong clinical evidence.” CardioDx announced the completion of a $58-million financing just less than two weeks after the August 8 announcement of coverage approval from Palmetto. The company is currently focused on expanding adoption of the test but is also looking at developing new tests, including one that would work in individuals with diabetes and another to help diagnose arrhythmia. Malorye Allison Acton, Massachusetts Box 1 Medicare covers cardiac gene signature test

Companies in footrace to deliver RNAi.

Ventures focusing on gene therapy, adoptive T-cell therapy, protein homeostasis and the microbiome are among those selected by the editors in 2013's crop of startups.

Nature Biotechnology 's academic spinouts of 2013

Amgen and collaborators UCB Pharma have said their investigational osteoporosis agent romosozumab met its main goal in late-stage trials. At ENDO 2016, the Endocrine Society’s annual meeting in Boston, the companies released data from phase 3 trials with romosozumab, a humanized monoclonal antibody that inhibits sclerostin. Results from 10,000 postmenopausal women with osteoporosis show that romosozumab promotes bone formation, increasing bone-mineral density measured at the hip and spine, and topping results obtained with Eli Lilly’s parathyroid hormone replacement therapy Forteo (teriparatide). But whether Amgen/UCB anti-sclerostin agent romosozumab might change standard-of-care treatment for osteoporosis will depend on longterm data on the drug’s ability to improve fracture healing. The phase 3 “STRUCTURE” trial with romosozumab reported a 2.6% improvement in hip bone mass density over 12 months, compared with a 0.6% loss with Forteo. The enhanced bone formation is clinically meaningful, says Taher Mahmud, consultant rheumatologist at the Maidstone and Tunbridge Wells NHS Trust, UK. The estimated hip strength also improved with romosozumab over 12 months, whereas it decreased with Forteo. Although positive, Amgen/UCB build on bone franchise with anti-sclerostin antibody

/pdf/white-house-unveils-national-microbiome-initiative-4lil1x3vh9.pdf

White House unveils National Microbiome Initiative

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