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Release: Sept. 16, 2002

UI team develops novel method to silence genes in mice

University of Iowa scientists have for the first time combined gene therapy strategies and a process that interferes with gene expression to silence, or turn off, genes in living animals (mice). The gene-silencing process, which occurs naturally in many organisms, is known as RNA interference.

The UI study could provide a basis for new antiviral therapies and treatments for certain inherited genetic diseases. The technique also could help researchers understand the functions of newly identified genes. The study appears in the Sept. 16 early online release from the journal Nature Biotechnology.

Normally, when a gene is turned on, or expressed, a series of events is set in motion, which results in the production of a protein. However, RNA interference disrupts gene expression by targeting an intermediate molecule called mRNA for degradation. Specifically, a hairpin-shaped molecule called small interfering RNA (siRNA) binds to mRNA, causing its removal. As a result, little or no protein is produced and thus gene expression is silenced. Such silencing could be useful to prevent the production of proteins that are harmful to the body.

In particular, the ability to selectively turn off certain genes would be useful in the treatment of many human diseases including viral diseases and certain genetic disorders. However, in order to use RNA interference to silence genes in specific tissues in the body, a way to instruct cells to make the appropriate interfering molecule had to be developed.

Beverly Davidson, Ph.D., the Roy J. Carver Chair in Internal Medicine, and colleagues, used their expertise to build a gene therapy vector to deliver genetic information into cells of mice and thus direct those cells to make specific siRNA molecules.

"Our experiments showed that we could decrease expression of genes that are normally expressed in a mouse and decrease expression of genes that are over-expressed in a transgenic mouse," Davidson explained. "This is the first time this gene silencing technique has been used with a gene transfer vector, and it is the first time it has been applied to animal tissues, indicating that it might be useful for therapeutic purposes."

Specifically, the UI team silenced genes in the brains and livers of mice. Davidson, who also is a UI professor in internal medicine, neurology, and physiology and biophysics, suggested that one possible siRNA-based therapy might be reducing the viral load of hepatitis in the liver. siRNA delivered by gene therapy to liver cells would silence genes associated with the viral infection.

The technique also could have important therapeutic implications for dominant inherited diseases. These are genetic diseases where one mutated copy of a gene (inherited from one parent) dominates the normal gene (inherited from the other parent) and causes the genetic disorder in the offspring.

The team used siRNA to decrease gene expression in a cell model of a group of dominantly inherited neurodegenerative diseases called the polyglutamine expansion diseases. At least nine diseases, including several spinocerebellar ataxias and Huntington's Disease, are caused by polyglutamine expansion.

The genetic defect in these diseases produces a mutated protein with an abnormally long stretch of the amino acid, glutamine. Expansion of this polyglutamine domain makes the protein toxic to brain cells, causing the protein to clump together as aggregates.

The team used gene therapy to make a specific siRNA molecule in brain cells that were producing a polyglutamine disease protein. The level of gene expression and thus the amount of toxic protein was significantly reduced, and fewer protein aggregates formed.

Davidson explained that knocking down the level of mutated protein in these polyglutamine disorders could provide a way to prevent the damage caused by these neurodegenerative diseases.

"We know from animal studies that if you modestly reduce levels of the mutated gene copy, you have a dramatic impact on disease severity," Davidson said.

The UI study showed that siRNA could distinguish between the mouse and human version of a gene. Davidson added that the experiments lay the foundations for investigators to precisely target siRNA to specific tissues or cell types, so that interfering RNA is turned on only in those places.

"siRNA seems to work for many different genes in multiple cell types and can be refined and optimized so that it knocks down the level of protein expression from the targeted gene to very, very low levels," Davidson said. "What's most exciting is the possibility of using this technique for therapeutic purposes and for studies to understand the function of newly identified genes and what their role is in the development of disease."

In addition to Davidson, the UI team included Haibin Xia, Ph.D., assistant research scientist, and Qinwen Mao, Ph.D., research investigator, who are lead authors of the study, and Henry Paulson, M.D., Ph.D., assistant professor of neurology. The study was funded by the National Institutes of Health and the Roy J. Carver Trust.

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