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Front Page

Modified Antibody Carries Cancer-fighting RNA To Tumor Cells in Mice

Modified Antibody Carries Cancer-fighting RNA to Tumor Cells in Mice

A new way to administer therapeutic RNA molecules that efficiently guides them to cells throughout the body has been reported by HMS researchers. The technique couples the homing ability of antibodies and an avid RNA-binding protein from sperm to deploy the RNAs in the bloodstream, where they can find and slip into their target cells.

Photo by Graham Ramsay

Judy Lieberman, Wayne Marasco, and colleagues have developed a way to target disease-fighting strands of RNA to certain genes within certain cells, speeding the therapeutic use of RNA interference.

The technique will speed the clinical application of RNA interference (RNAi), a recently discovered process of selective gene silencing that is expected to yield exquisitely focused therapies for many human diseases, including cancer and AIDS. Development of RNA therapeutics has been hung up on the practical matter of how to deliver these drugs to inaccessible organs and tissues, and do so in a way that cells will be able to absorb them.

“This method allows us to inject an RNA drug intravenously and get it throughout the body, and then to deliver it to certain cells very specifically and with very high efficiency,” said Judy Lieberman, HMS professor of pediatrics at the CBR Institute for Biomedical Research and principal investigator on the study.

Lieberman and her colleagues used their new system to show for the first time that infusing small interfering RNAs (siRNAs) coupled to cancer-seeking antibodies slows the growth of tumors in mice while leaving the surrounding normal tissue untouched. The researchers also demonstrate that siRNAs targeted to HIV-infected T cells, but not healthy T cells, block viral growth. Their work appeared online May 22 in Nature Biotechnology.

“We are developing reagents that are useful for targeting immune cells, erythroid cells, liver cells, and brain cells. The ability to target antibodies is pretty unlimited, and that’s why it’s so attractive, since we can think of whole classes of disease where the RNA interference approach might be useful,” Lieberman said.

Kiss of Death
RNAi therapies are based on a natural cell process that controls the fundamental flow of information in cells: the genetic code contained in DNA is translated into messenger RNA, which then makes proteins. siRNAs silence genes by binding to messenger RNA and marking it for destruction. Because RNA, like DNA, is composed of repeating bases that define a unique pattern for each gene, siRNAs can be synthesized in the laboratory to match any gene sequence. This gives researchers the ability to come up with a therapeutic RNA that turns off just one disease-causing gene in an organism while leaving normal genes untouched.

To disburse these potentially powerful medicines, the researchers engineered human antibodies to carry their siRNA cargo by adding protamine, a protein long recognized for its prodigious DNA-carrying ability. Protamine abounds in sperm, where it functions to compress long DNA molecules into the tiny package that will eventually be delivered to the egg. The antibody–protamine fusions were first developed ten years ago by Wayne Marasco, an HMS associate professor of medicine at the Dana–Farber Cancer Institute and a co-author on the paper. “We were using the antibodies to deliver DNA to cells for gene therapy, but we recognized early on that this protein could carry RNA as well as DNA,” Marasco said.

The Double Smart Drug
Compared to other delivery systems, the antibody-based method is safer, offers more flexibility, and delivers more active siRNA to cells, according to Lieberman, who, in 2003, was the first to successfully use RNAi in an animal. In that study, delivery of the RNAi to mice required pumping the solution into the blood under high pressure, a procedure that is too dangerous to use in humans. The new technique does not carry such risk, and in fact, the researchers saw no signs of toxicity after infusion of their antibody–siRNA complex.

Since the siRNA binds protamine reversibly, antibodies and siRNAs can easily be mixed and matched to any disease situation. “It’s possible to change the specificity of the antibody, or change the siRNA, or use a cocktail of siRNAs. For example, if a patient had a tumor and it mutated, you could quickly tailor the delivery to the new situation,” Lieberman explained.

This represents a “very exciting advance” in developing smart drugs based on RNA interference to attack specific genetic defects in cells, said Nobel laureate and RNA expert Phillip Sharp of MIT. “The antibody coupled to siRNA might be called a doubly smart drug, where there is smart targeting of the antibody to the surface of a particular cell and smart targeting of the siRNA to a particular gene within the cell.”

Lieberman’s antibody-based delivery has caught the attention of pharmaceutical companies developing siRNA-based drugs. “Many companies, including ours, are interested in novel strategies for delivery of siRNAs to specific cells and tissues,” said John Maraganore, president of Cambridge-based Alnylam Pharmaceuticals. “While there’s more to do, this technology could be useful to develop therapeutics, especially for cancer and certain viral diseases.”

—Pat McCaffrey

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