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Photocaging to Control RNAi


While a number of technologies are being developed to turn the RNAi process on and off, these typically require introducing small molecules or other compounds into the cell. But a researcher from Louisiana State University thinks that a photoactivation technique developed three decades ago may offer a better solution.

The approach, called photocaging, involves covalently attaching blocking groups onto a nucleic acid. These groups keep the nucleic acid inert — an siRNA, for instance — while protecting it from enzymatic degradation until it is exposed to light, at which point the nucleic acid's activity is restored, according to Todd Monroe, an assistant professor in LSU's department of biological and agricultural engineering.

"There are a lot of small molecules that can drive gene expression or gene repression, but those molecules, if they are not already inherent in some type of pathway, have to be delivered" and can be difficult to regulate, he says.

With photocaging, on the other hand, researchers can control when and where in a cell a nucleic acid is activated, he says. "If we're working with an organism instead of a culture dish, we can deliver [a caged nucleic acid] in a select spot," such as the retina.

According to Monroe, photocaging was developed in the 1970s to inactivate and reactivate ATP to study the kinetics of muscle contraction. "We'd like to take those same principles [used with ATP] and apply them in cells and tissues to govern nucleic acid bioactivity," he says.

Monroe and his colleagues have been working on this concept for some time and have conducted experiments in which they attached nitro benzyl-like cage compounds to the phosphate backbone of DNA. This caging process "disrupts transcriptional enzyme machinery [and] blocks [the DNA's] degradation by nucleases," he explains. When exposed to light, the molecules reactivated.

— Doug Macron

RNAi Notes

Intradigm licensed the rights to the Massachusetts Institute of Technology's nucleic acid delivery patent. This covers a range of biodegradable polymer structures used to deliver RNAi-based therapeutics.
In a filing with the US Securities and Exchange Commission, Arrowhead Research said its subsidiaries, Calando Pharmaceuticals, an RNAi drug firm and Insert Therapeutics, a nanobiotech company, will merge.

Alnylam Pharmaceuticals announced that a double-blind, placebo-controlled, randomized study showed that its siRNA-based respiratory syncytial virus drug ALN-RSV01 is safe and well-tolerated. The results are to be presented at the International Symposium on Respiratory Viral Infections meeting.


$7.5 million
Introgen Therapeutics, which develops tumor suppressor drugs, sold its approximately 7.5 million shares of Silence Therapeutics, netting $7.5 million.

Funded grants

Developing RNA Interference for Gene Specific Silencing in Aplysia Neurons
Grantee: Kelsey Martin, UCLA
Began: Apr. 1, 2007; Ends: Mar. 31, 2009
With this grant, the researchers want to develop RNAi for use in Aplysia neurons. To determine if the silencing will work, they will target four endogenous Aplysia genes and exogenously overexpressed destabilized eGFP. The researchers say that the ability to use RNAi in Aplysia will also yield information about molecular mechanisms underlying synapse formation, synaptic transmission, and synaptic plasticity.

Novel tumor suppressor gene discovery in pancreatic cancer
Grantee: James Eshleman, Johns Hopkins University School of Medicine
Began: Sep. 1, 2007; Ends: Aug. 31, 2009
In this grant, the researchers propose to use RNAi to uncover novel pancreatic cancer tumor suppressor genes. First, they plan to construct cell lines by transducing non-tumorigenic and weakly tumorigenic pancreas cell lines with whole-genome libraries. Then, they will select tumorigenic cell clones and perform sequencing.

The Scan

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