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Strands: Mar 19, 2009


Cenix Begins Target Validation Work for AstraZeneca

Cenix BioScience announced this week that it has begun a second research project under an existing arrangement with AstraZeneca.

According to Cenix, the new project will focus on cell-based studies to advance the validation of novel oncology-target candidates recently identified by the company in RNAi screens conducted for AstraZeneca.

Specific terms of the new agreement were not disclosed.

RXi Q4 Losses Rise on Higher R&D Spending, Delivery Technology License

RXi Pharmaceuticals this week reported its fourth-quarter financial results, posting increased losses on higher research and development spending.

The company's net loss for the quarter ended Dec. 31 rose to $4 million, or $0.29 per share, from $2.6 million, or $0.21 per share, in the same period a year earlier.

Driving the losses up was a jump in R&D costs to $2 million from $1.4 million the year before, an increase RXi attributed in part to the cost of licensing the so-called glucan-encapsulated siRNA particles, or GERP, technology from the University of Massachusetts Medical School late last year (see RNAi News, 10/16/2008).

Meanwhile, general and administrative expenses climbed to $2 million from $1.4 million in the year-ago period.

At the end of 2008, RXi had cash and cash equivalents totaling about $9.8 million.

Dicerna Obtains Exclusive Right to Sublicense Dicer-Substrate Tech

Dicerna Pharmaceuticals said this week that it has obtained the exclusive, worldwide rights to sublicense its Dicer-substrate intellectual property for pharmaceutical uses, which the company had previously licensed from the City of Hope (see RNAi News, 11/8/2007).

"Going forward, Dicerna is the only company that can grant sublicenses" to the technology, Dicerna CEO James Jenson said in a statement.

Specific details of the deal, including the organization from which Dicerna obtained the sublicense rights, were not disclosed.

Currently, only two other companies hold rights to the Dicer-substrate technology, which was co-developed by investigators at the City of Hope and Integrated DNA Technologies: in late 2006, MDRNA, formerly known as Nastech Pharmaceutical, announced that it had exclusively licensed the technology from City of Hope for use against five undisclosed targets (see RNAi News, 11/9/2006).

Earlier this year, MDRNA non-exclusively licensed a portion of its technology platform, including the Dicer-substrates, to Roche (see RNAi News, 2/19/2009).

Intradigm Says USPTO to Award Patent on siRNA Sequence

Intradigm announced this week that it has been notified that the US Patent and Trademark Office will grant the company a patent covering certain aspects of a specific siRNA sequence with potential use in treating cancer.

Specific details about the intellectual property were not provided, but Intradigm said that the sequence targets angiogenesis.

Integrated DNA Technologies Purchases VH Bio's Oligo Business

Oligonucleotide synthesis company Integrated DNA Technologies this week announced that it has purchased VH Bio's oligonucleotide business.

Under the agreement, IDT will serve VH Bio's oligonucleotide customers from IDT's European synthesis facility, which opened in Leuven, Belgium, this past September. As such, IDT plans to provide current VH Bio customers with a broader product range of quality-controlled oligonucleotides that are available for next-day delivery.

Financial terms of the agreement were not disclosed.

IDT and VH Bio, which is based in Gateshead, UK, also announced that they plan to work together to expand IDT's oligonucleotide business in the UK. VH Bio will continue distributing its other products, including those for immunologists and molecular biologists.

Asuragen Certified for Agilent Assays

Agilent Technologies said this week that it has certified Asuragen to offer its array-based comparative genomic hybridization and microRNA assays along with its lab services offerings.

Agilent named Asuragen a certified service provider for these assays after a training and assessment program that included proficiency in analyzing Agilent's 60-mer oligo microarrays, providing sample quality control on the Agilent 2100 Bioanalyzer, using its reagents and protocols, scanner and extraction software, and using the GeneSpring bioinformatics platform for data analysis.

"Agilent's miRNA microarrays and Array CGH for DNA allow us to add another dimension to our comprehensive oncology services and Encompass for FFPE (Formalin-fixed, paraffin-embedded) Tissues Services portfolios for our clients," Carol Berry, GM of Asuragen's Pharmaceutical Services Division, said in a statement.

Team Reports microRNA Profile Predicts Acute Kidney Transplant Rejection

In a paper appearing online this week in the Proceedings of the National Academy of Sciences, a team of American and French scientists identified a microRNA expression profile that can predict which kidney transplant patients will suffer acute transplant rejection and reduced transplant function.

Using arrays, the researchers identified more than a dozen miRNAs that were differentially expressed in cases of acute kidney transplant rejection compared to stable transplants. They subsequently validated six of these in a larger, independent cohort, linking miRNA levels to both acute rejection and transplant function.

Interestingly, rejection samples and peripheral blood mononuclear cells shared some highly expressed miRNAs, while miRNAs that were under-represented in rejection samples were found at high levels in primary human kidney epithelial cells. Together, the results support the idea that kidney transplant rejection occurs as recipient immune cells enter and attack transplanted tissue.

Along with such insights, the team suggested that miRNAs may also serve as markers for kidney transplant or renal allograft status.

"Our studies, in addition to suggesting a cellular basis for the altered intragraft expression of miRNAs, propose that miRNA expression patterns may serve as biomarkers of human renal allograft status," senior author Manikkam Suthanthiran, a nephrology and transplantation researcher at the New York-Presbyterian-Weill Cornell Medical Center, and his colleagues wrote.

Although organ transplantation has become fairly routine, transplant recipients must continue taking immunosuppressive drugs throughout their lives to prevent transplant rejection. Such rejection occurs when the recipient's immune system recognizes the transplant as foreign and mounts an immune response against it.

Because previous research suggests gene expression — including the expression of genes involved in immunity, cell cycle control, and metabolism — shifts dramatically during transplant rejection, Suthanthiran and his team decided to look at whether they could find miRNA expression changes that heralded acute transplant rejection.

They evaluated 33 transplanted tissue or allograft biopsies, taken from 32 adults who had had kidney transplants — a dozen from 11 individuals with acute rejection and graft dysfunction and 21 from individuals with stable transplanted kidney function.

From these, the team initially evaluated miRNA profiles in three of the acute rejection biopsy samples and four stable transplant samples using an Applied Biosystems TaqMan low-density array human microRNA panel representing 365 mature human miRNAs.

They found roughly 174 miRNAs expressed in each of the samples. But the same miRNAs were not present in all of the biopsies. The researchers identified 17 miRNAs that were expressed at different levels in the acute rejection samples than they were in the stable transplant samples. Of these, ten were under-expressed and seven were over-expressed in the acute rejection samples.

Using modified TaqMan miRNA assays, the researchers confirmed the differential expression of six of the miRNAs in an independent validation set of nine acute rejection and 17 stable transplant biopsy samples. The acute rejection samples showed increased expression of miR-142-5p, miR-155, and miR-223 and decreased expression of miR-10b, miR-30-3p, and let-7c.

All six miRNAs were also linked to the transplanted kidney's function, specifically glomerular filtration rate, though miR-142-5p and miR-10b were most strongly associated with this function.
Of the differentially expressed miRNAs, miR-142-5p and miR-155 seem to be the most promising biomarkers for predicting kidney transplant status. Both predicted acute rejection with 100 percent sensitivity and 90 percent to 95 percent specificity. The other four miRNAs, while diagnostic, predicted rejection less accurately.

When they used real-time quantitative PCR to assess messenger RNA levels in the transplant tissue, the team found that the levels of miR-142-5p, miR-155, and miR-223 correlated with the levels of mRNA for immune genes such as CD30 and CD20. Overall though, miRNA levels appeared to more accurately predict transplant rejection than CD3, CD20 or other mRNA levels tested.

Consistent with the notion that acute transplant rejection involves immune system infiltration of transplanted kidney tissue the team found that rejection miRNA profiles were more similar to normal human peripheral blood mononuclear cells than to primary human kidney epithelial cells.
And miRNAs previously linked to immune system function were among those that were highly expressed in rejection samples whereas miRNAs that appear to contribute to kidney tubule function were down-regulated.

The researchers say even more research is needed to understand just how miRNA profiles are altered in the graft-infiltrating and transplant epithelial cells. But, they added, their results suggest miRNA expression patterns may be a promising tool for predicting and monitoring patients' kidney transplant status.

Researchers ID miRNA Involved in Innate Immune Response

An Italian research team this week published data showing that a specific miRNA appears to be involved in the innate immune response by helping to regulate cellular responses that depend on the transcription factor complex NF-kappa-B.

The researchers, who reported their findings online in the Proceedings of the National Academy of Sciences, assessed miRNA levels in two types of human immune cells — monocytes and polymorphonuclear neutrophils — exposed to inflammation-stimulating bacterial lipopolysaccharides or LPS for several hours. Although more than a dozen miRNAs were up-regulated in either human monocytes or PMN following LPS exposure, the team found just one that was up-regulated in both: miR-9. Based on their subsequent experiments, they propose that miR-9 targets the NF-kappa-B sub-unit NFKB1 tempering the NF-kappa-B-dependent immune response.

In contrast to adaptive immunity, which "remembers" infectious agents from previous exposure, innate immunity provides first-line protection against infectious agents. For instance, the components of the innate immune system can use inflammation and phagocytosis to get rid of cellular debris and/or pathogens that enter the body.

Since microRNAs, a group of 22-nucleotide, non-protein coding regulatory RNAs, have been implicated in everything from development to immunity to tumor formation, senior author Massimo Locati, a researcher at the University of Milan's Department of Translational Medicine, and his team decided to look at the miRNAs involved in human innate cell response to bacterial LPS.
Specifically, the researcher used a TaqMan-based low density array to assess miRNAs in two types of innate immune cells — PMN and monocytes — that had been stimulated with LPS for eight hours.

Their search turned up a dozen miRNAs that were up-regulated in one of the cell types. But when the team used RT-qPCR time course analyses to follow up on their initial experiments they found that just one miRNA — miR-9 — was up-regulated in both PMN and monocytes. Their subsequent experiments suggest adding LPS triggers miR-9 induction via an immune pathway containing the adaptor protein MyD88 and NF-kappa-B.

Although miR-9 precursors are encoded by three different genes: Clorf61, BC036480, and CR612213, the researchers found that LPS treatment only ramped up the level of pri-miR-9-1, the primary transcript encoded by Clorf61.

Next, the team looked for miR-9 targets using miRGen, a public database of animal miRNAs and their predicted targets. They found potential miR-9 targets in the transcription regulators Onecut2 and PRDM1/Blimp-1. But since neither regulator is expressed in the two cell types tested, though, the researchers instead focused on another potential miR-9 target: NFKB1, which codes for the NF-kappa-B p50 subunit and its precursor p105.

Consistent with this, the researchers demonstrated that miR-9 curbs NF-kappa-B activity. In addition, their research suggests that, while more NFKB1 transcripts are present in LPS-stimulated PMN and monocytes, there is no comparable rise in NFKB1 protein products. That, in turn, suggests post-transcriptional regulation of the gene, possibly by miR-9.

Overall, the researchers concluded that miR-9 — previously shown to influence neuronal development and function in the mammalian brain and to regulate insulin- and B-cell related transcription factors outside the central nervous system — has a role in tweaking NF-kappa-B levels during the pro-inflammatory phase of innate immunity.

"Since [NF-kappa-B] is a key regulator of inflammation, the [NF-kappa-B] levels are likely to be a strictly controlled and timely regulated event of relevance for the proper progression of the inflammatory response," the authors wrote.

"On the basis of our observations it is tempting to propose a model in which the parallel [NF-kappa-B]-dependent induction of NFKB1 and miR-9 provides a mean to smooth out the fluctuations in gene expression and fine tune the synthesis of this key transcription factor, thus allowing the pro-inflammatory phase of the LPS response to correctly proceed."

The Scan

Study Tracks Off-Target Gene Edits Linked to Epigenetic Features

Using machine learning, researchers characterize in BMC Genomics the potential off-target effects of 19 computed or experimentally determined epigenetic features during CRISPR-Cas9 editing.

Coronary Artery Disease Risk Loci, Candidate Genes Identified in GWAS Meta-Analysis

A GWAS in Nature Genetics of nearly 1.4 million coronary artery disease cases and controls focused in on more than 200 candidate causal genes, including the cell motility-related myosin gene MYO9B.

Multiple Sclerosis Contributors Found in Proteome-Wide Association Study

With a combination of genome-wide association and brain proteome data, researchers in the Annals of Clinical and Translational Neurology tracked down dozens of potential multiple sclerosis risk proteins.

Quality Improvement Study Compares Molecular Tumor Boards, Central Consensus Recommendations

With 50 simulated cancer cases, researchers in JAMA Network Open compared molecular tumor board recommendations with central consensus plans at a dozen centers in Japan.