Team demos safety of RNA therapy

September 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.

The work, which will be published in the Sept. 27 issue of Nature, describes a new approach to conducting the therapy. A paper in Nature last year reported that another commonly used approach caused fatalities in mice.

The research focuses on RNA interference, or RNAi, a key part of the body's genetic machinery. RNAi works by using short strands of RNA to block the expression of specific genes.

“RNAi has huge potential as a therapeutic agent,” said Daniel Anderson, a research associate at MIT's Center for Cancer Research and one of the authors of the new paper.

However, a paper published in Nature last year by a different team showed that large doses of one type of RNA used for RNAi, short hairpin RNA, disrupted another key RNA pathway, the microRNA pathway, and caused the mice in the study to die. That result worried some RNAi researchers, said Anderson.

“That first paper demonstrated that short hairpin RNA could lead to mouse fatality,” he said. “Researchers were concerned that a second type of RNA, small interfering RNA (siRNA), would induce the same toxicity.”

In the current study, the researchers demonstrated that siRNA did not have the same toxic effects as large doses of shRNA because it does not interfere with the microRNA pathway. Further, they achieved 80 percent silencing of target genes in mice and hamster liver cells.

“Using chemically synthesized siRNA, you can deliver sufficient siRNA to achieve therapeutically valuable gene silencing, without interfering with the cell's endogenous microRNA,” said David Bumcrot, a director of research at Alnylam (an MIT startup) and one of the authors of the paper.

The research team used a new RNA delivery system developed at MIT, the details of which will be published in another upcoming paper, to perform the RNA interference.

In many RNAi studies, including the one that the MIT/Alnylam team was following up on, researchers use retroviruses to deliver genes that code for short hairpin RNA, which is a precursor to siRNA. Once the gene is incorporated into the cell's DNA, short hairpin RNA is synthesized and transported from the cell nucleus to the cytoplasm for further processing.

The earlier study showed that large amounts of short hairpin RNA blocked the cell's ability to export microRNA, which uses the same export pathway. Without normally functioning microRNA, the mice died. Low doses of short hairpin RNA were not toxic, but the dosage is difficult to control because once the shRNA gene is incorporated into the DNA of the host cells, it is expressed for long periods of time, said Bumcrot.

In the current MIT/Alnylam study, siRNA was delivered directly to the cell cytoplasm, so it did not compete with the export of microRNA.

“We wanted to demonstrate that if you go downstream of that (export) step in the pathway, you don't get interference with the microRNA pathway,” said Bumcrot. “With synthetic siRNAs, we deliver a defined dose and we know how long the effect lasts. If toxicity issues arise, dosing can be stopped at any time. It's much easier to control and, therefore, safer.”

Source: Massachusetts Institute of Technology

Explore further: Scientists analyze viability of shRNA therapy for Huntington's Disease

Related Stories

Scientists analyze viability of shRNA therapy for Huntington's Disease

December 1, 2017
Researchers from the Biogerontology Research Foundation , Department of Molecular Neuroscience at the Swammerdam Institute for Life Sciences at the University of Amsterdam, and the Department of Neurobiology, Care Sciences ...

How can CRISPR genome editing shape the future of cancer research?

January 12, 2018
The genome editing technology CRISPR is causing plenty of excitement in cancer research.

Synthetic RNAs designed to fight cancer

December 6, 2013
(Medical Xpress)—In search of better cancer treatments, researchers at Washington University School of Medicine in St. Louis have designed synthetic molecules that combine the advantages of two experimental RNA therapies.

Delivering RNA with tiny sponge-like spheres

February 27, 2012
For the past decade, scientists have been pursuing cancer treatments based on RNA interference — a phenomenon that offers a way to shut off malfunctioning genes with short snippets of RNA. However, one huge challenge ...

Ovarian cancer growth inhibited by nanoparticle delivery of EGFR siRNA

November 7, 2016
In the fight against cancer, doctors dish out combination-blows of surgery, chemotherapy and other drugs to beat back a merciless foe. Now, scientists have taken early steps toward adding a stinging punch to clinicians' repertoire.

Ultrasound waves propel rapid delivery of RNA to treat colon inflammation

January 20, 2017
MIT and Brigham and Women's Hospital researchers have demonstrated that they can deliver strands of RNA efficiently to colon cells, using bursts of ultrasound waves that propel the RNA into the cells. Using this approach, ...

Recommended for you

15 new genes identified that shape human faces

February 20, 2018
Researchers from KU Leuven (Belgium) and the universities of Pittsburgh, Stanford, and Penn State have identified 15 genes that determine facial features. The findings were published in Nature Genetics.

New algorithm can pinpoint mutations favored by natural selection in large sections of the human genome

February 20, 2018
A team of scientists has developed an algorithm that can accurately pinpoint, in large regions of the human genome, mutations favored by natural selection. The finding provides deeper insight into how evolution works, and ...

New software helps detect adaptive genetic mutations

February 20, 2018
Researchers from Brown University have developed a new method for sifting through genomic data in search of genetic variants that have helped populations adapt to their environments. The technique, dubbed SWIF(r), could be ...

Highly mutated protein in skin cancer plays central role in skin cell renewal

February 20, 2018
Approximately once a month, our skin completely renews itself. If this highly coordinated process goes awry, it can lead to a variety of skin diseases, ranging from skin cancer to psoriasis. Cells lining such organs as skin ...

Study of smoking and genetics illuminates complexities of blood pressure

February 15, 2018
Analyzing the genetics and smoking habits of more than half a million people has shed new light on the complexities of controlling blood pressure, according to a study led by researchers at Washington University School of ...

New mutation linked to ovarian cancer can be passed down through dad

February 15, 2018
A newly identified mutation, passed down through the X-chromosome, is linked to earlier onset of ovarian cancer in women and prostate cancer in father and sons. Kunle Odunsi, Kevin H. Eng and colleagues at Roswell Park Comprehensive ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.