Researchers report oral delivery system for RNAi therapeutics

Apr 29, 2009

Researchers at the University of Massachusetts Medical School (UMMS) report today on a novel approach to the delivery of small bits of genetic material in order to silence genes using "RNA interference"—and in the process, discovered a potent method of suppressing inflammation in mice similar to what occurs in a range of human diseases.

In the April 30, 2009 issue of the journal Nature, Professor Michael P. Czech, PhD, and colleagues in the Program in Molecular Medicine at UMMS describe the engineering of small encapsulating particles containing short pieces of RNA that dramatically silenced genes in mice following oral administration in small doses. The paper, "Orally delivered siRNA targeting macrophage MAP4K4 suppresses systemic inflammation," provides a possible pathway to address the most common—and daunting—challenge in the new field of RNA therapeutics: how to deliver the short strands of RNA used in gene silencing to specific tissues and cell types.

"We are very encouraged by these results, which show that oral delivery of a therapeutic dose of small, interfering RNA (siRNA) to a specific cell type in an animal model is possible, and that evidence of gene silencing using this delivery system is measurable," said Dr. Czech.

The discovery in 1998 that short strands of RNA can silence the action of a given gene changed the scientific world's understanding of how genes are regulated. Highly specific and highly potent, "" or "RNAi" has become both a crucial laboratory technique and widely studied for potential therapeutic applications; the explanation of the mechanism of RNAi was recognized with the 2006 in Medicine, awarded to UMMS Professor Craig C. Mello, PhD, and collaborator Andrew Z. Fire, PhD, of Stanford University; since the discovery, laboratories around the world have focused on the potential of RNAi to silence genes with high specificity, low toxicity and minimal immune system response.

But how to deliver tiny strands of genetic material into cells in a living organism has been a formidable obstacle. In this paper, Czech and colleagues chose to target a particular type of cell in the immune system called a "macrophage," a type of white blood cell that engulfs and digests cellular debris and responds to invading organisms by stimulating the immune response. Because macrophages control the inflammatory response in diseases such as rheumatoid arthritis and atherosclerosis (a precursor to heart disease), they represent an attractive target for drug delivery.

To move short strands of into the macrophages, the researchers exploited a distinctive characteristic of yeast particles: the ability to be engulfed and digested by macrophages. By using these yeast particles as a delivery shell, they were able to deliver siRNAs targeting a gene known for its key role in the inflammatory response—and turn it off. The macrophages carrying the RNAi moved throughout the organism as they circulated from the digestive system (where they first encountered the particles and engulfed them) with the result that over time, a large portion of the organism's macrophages exhibited gene silencing.

The method of treating yeast particles to remove components that would cause an immune response and generate oral delivery vehicles composed of "beta1,3-D glucan" was developed by UMMS research professor and paper co-author Gary R. Ostroff, PhD. The method of using glucan particles as a drug delivery system has been tested in a number of animal models. In December 2008, the Massachusetts Life Sciences Center awarded a three-year, $750,000 cooperative research grant to UMMS and biotech startup RXi Pharmaceuticals to investigate the development of a range of orally delivered RNAi therapeutics using the glucan particle model. (RXi was co-founded by Nobel Laureate Mello, who serves on its Scientific Advisory Board, and Czech.)

In the series of experiments, the researchers were able to silence gene expression both in vitro and in vivo, in a mouse model, at a range of doses and concentrations; oral delivery of as little as 20 micrograms per kilogram of body weight of siRNA silenced a signaling protein called MAP4K4, a key player in the inflammatory response in disease processes like arthritis. (By contrast, research studies evaluating intravenous injections of siRNAs often used concentrations from 12 to 500 times higher.)

"In the future, this paper will be viewed as a landmark in the process of translating RNAi into effective new therapies for human diseases," said Terence R. Flotte, MD, dean of the school of medicine at UMMS. "It addresses one of the most fundamental problems in the field, that of delivery of the RNAi molecule to the cells affected by the disease process."

Source: University of Massachusetts Medical School (news : web)

Explore further: First genetic link discovered to difficult-to-diagnose breast cancer sub-type

add to favorites email to friend print save as pdf

Related Stories

Team demos safety of RNA therapy

Sep 26, 2007

Researchers from MIT, Alnylam Pharmaceuticals and other institutions have demonstrated the safety of a promising type of genetic therapy that could lead to treatments for a wide range of diseases such as cancer.

Team develops safe, effective RNA interference technique

Apr 28, 2008

A team of researchers from MIT and Alnylam Pharmaceuticals has developed safe and effective methods to perform RNA interference, a therapy that holds great promise for treating a variety of diseases including ...

The RNA drug revolution -- a new approach to gene therapy

Jan 23, 2008

RNA interference (RNAi) represents an innovative new strategy for using small RNA molecules to silence specific genes associated with disease processes, and a series of review articles describing the state-of-the-art and ...

'Silencing' HIV with small bits of RNA

Aug 07, 2008

Researchers have shown that they can effectively tackle HIV-1 with small bits of gene-silencing RNA by delivering them directly to infected T cells, the major targets of the virus. While earlier studies had shown such a strategy ...

RNAi shows promise in gene therapy, researcher says

Feb 19, 2007

Three years ago Mark Kay, MD, PhD, published the first results showing that a biological phenomenon called RNA interference could be an effective gene therapy technique. Since then he has used RNAi gene therapy to effectively ...

Recommended for you

Refining the language for chromosomes

Apr 17, 2014

When talking about genetic abnormalities at the DNA level that occur when chromosomes swap, delete or add parts, there is an evolving communication gap both in the science and medical worlds, leading to inconsistencies in ...

Down's chromosome cause genome-wide disruption

Apr 16, 2014

The extra copy of Chromosome 21 that causes Down's syndrome throws a spanner into the workings of all the other chromosomes as well, said a study published Wednesday that surprised its authors.

User comments : 0

More news stories

Filipino tests negative for Middle East virus

A Filipino nurse who tested positive for the Middle East virus has been found free of infection in a subsequent examination after he returned home, Philippine health officials said Saturday.

Study says we're over the hill at 24

(Medical Xpress)—It's a hard pill to swallow, but if you're over 24 years of age you've already reached your peak in terms of your cognitive motor performance, according to a new Simon Fraser University study.

NASA's space station Robonaut finally getting legs

Robonaut, the first out-of-this-world humanoid, is finally getting its space legs. For three years, Robonaut has had to manage from the waist up. This new pair of legs means the experimental robot—now stuck ...

Ex-Apple chief plans mobile phone for India

Former Apple chief executive John Sculley, whose marketing skills helped bring the personal computer to desktops worldwide, says he plans to launch a mobile phone in India to exploit its still largely untapped ...

Egypt archaeologists find ancient writer's tomb

Egypt's minister of antiquities says a team of Spanish archaeologists has discovered two tombs in the southern part of the country, one of them belonging to a writer and containing a trove of artifacts including reed pens ...

Airbnb rental site raises $450 mn

Online lodging listings website Airbnb inked a $450 million funding deal with investors led by TPG, a source close to the matter said Friday.