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Debate Continues Over Anti-Angiogenic siRNAs

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All siRNAs, including two that are currently in clinical development as treatments for wet age-related macular degeneration, suppress neovascularization regardless of their sequences or targets due to the activation of a cellular immune response, according to a paper appearing in Nature.

In the study, researchers from the University of Kentucky reported that any dsRNA at least 21 nucleotides in length activated toll-like receptor 3, which in turn suppressed angiogenesis in the retinas of a mouse in which a laser injury triggered choroidal neovascularization.

Among those siRNAs tested by the investigators were ones targeting the same sequences as the AMD drug candidates bevasiranib, which targets vascular endothelial growth factor and is being developed by Opko Health, and AGN211745, which targets VEGF receptor-1 and was licensed by Allergan from Sirna Therapeutics.

Though the paper raises questions about the mechanism by which these two RNAi drugs appear to be working, at least two industry insiders say it mostly reinforces what is already known: that RNA-based drugs have the potential to trigger an unintended immune response.

But Sam Reich, executive vice president of ophthalmologics at Opko, charged that the paper's findings, at least in regards to bevasiranib, are simply inaccurate and could be the result of the authors' use of a mouse model known to yield "variable outcomes."

"We respectfully disagree with the conclusions [the authors] have drawn," he says. "We stand by our data [that] shows that our molecule mediates VEGF silencing, which is anti-angiogenic, using the appropriate controls."

"Anyone who is practiced in the art is not surprised that toll-like receptors are involved in nucleic acid recognition and downstream signaling leading to interferon production, et cetera," says Alan Sachs, vice president of RNA therapeutics at Merck Research Laboratories.

 — Doug Macron

RNAi Notes

Cenix Bioscience will be conducting high-throughput RNAi screening experiments for AstraZeneca and CellCentric, an epigenetics firm. For AstraZeneca, Cenix will be looking for and validating oncology targets; meanwhile, for CellCentric, it will be validating several anti-cancer drug targets.

University College London and the Hospital for Sick Kids in Toronto joined Open Biosystems' Open Access RNAi program, which began in 2006 to make the genome-wide shRNA libraries more available to researchers.

Nastech Pharma-ceutical's public accounting firm, KPMG, sent a going concern qualification to the company to express its concerns about the drug developer's ability to continue operations.

Datapoint

384
Ambion's Silence Select siRNA libraries now come in 96- or 384-well plate formats. They are available as human kinases and phosphatases.

Funded Grants

$372,211/FY2007
RNAi in DNA Sequence Elimination in Tetrahymena
Grantee: Martin Gorovsky, University of Rochester
Began: May 1, 2007; Ends: Apr 30, 2011
Gorovsky will be using this grant to study and characterize how small RNAs mediate genome reorganization in Tetrahymena. This process, says the grant application, resembles eukaryotic heterochromatin formation. The researchers hope this work will also inform other research on similar RNAi-like mechanisms that help develop and maintain stable genomes.

$292,125/FY2007
New Frontiers for Small RNA Therapies
Grantee: Michael McManus, UCSF
Began: Feb 1, 2007; Ends: Jan 31, 2012
McManus and his lab will be using a mouse model to study RNAi pathways, especially the mechanism behind how small RNAs silence repetitive DNA. Also, they will be examining whether the position and sequence of the shRNA and target DNA are important for that silencing. They hope their mouse model will be helpful in testing the uptake and activity of siRNAs therapeutic for human disease.

The Scan

And Back

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Lacks Family Hires Attorney

A lawyer for the family of Henrietta Lacks plans to seek compensation from pharmaceutical companies that have used her cancer cells in product development, the Baltimore Sun reports.

For the Unknown

The Associated Press reports that family members are calling on the US military to use new DNA analysis techniques to identify unknown sailors and Marines who were on the USS Arizona.

PLOS Papers on Congenital Heart Disease, COVID-19 Infection Host MicroRNAs, Multiple Malformation Mutations

In PLOS this week: new genes linked to congenital heart disease, microRNAs with altered expression in COVID-19, and more.