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Investigators Explore Selective Silencing of Disease Genes

For release: Wednesday, October 15, 2003

A new strategy to shut down mutant gene expression in the brain may someday be useful to treat a wide range of hereditary neurodegenerative diseases, such as Huntington’s, Alzheimer’s, and Parkinson’s diseases.

In a study by Henry Paulson, M.D., Ph.D., along with graduate student Victor Miller and colleagues from the University of Iowa, researchers engineered cells to produce both normal and mutant versions of genes associated with two rare but devastating inherited neurodegenerative disorders: Machado-Joseph disease, also called spinocerebellar ataxia type 3, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The study was reported in the June 10, 2003 issue of The Proceedings of the National Academy of Sciences, USA,* and was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).

Machado-Joseph disease results from a “CAG repeat mutation,” an abnormal repetition of three letters in the DNA genetic code. Symptoms include vision problems, slow movement, stiffness, hand tremor, and problems with balance and coordination. The mutation causes proteins to be made with abnormally long strings of the amino acid glutamine; these proteins are toxic to neurons. This “polyglutamine” problem is the root of several other disorders, including Huntington’s disease, myotonic dystrophy, and other forms of ataxia.

FTDP-17 is the result of an inherited mutation in the gene sequence for tau, which normally makes essential proteins in the brain. Tau proteins help keep neurons alive by stabilizing the structure inside the cell. As in Alzheimer’s disease, abnormal tau proteins form large clumps, called neurofibrillary tangles, and lose their ability to bind structural components inside neurons. Symptoms of FTDP-17 include a lack of impulse control (disinhibition) and some Parkinson-like features. For FTDP-17 and Machado-Joseph disease, and many other neurodegenerative disorders, there are currently no cures, only treatments for some of the symptoms.

In the Iowa study, researchers introduced the mutated and normal versions of these genes into laboratory cell cultures. Then, in an attempt to turn off only the mutant genes, the researchers used a technique called RNA interference. This technique uses small fragments of genetic material (called small interfering RNA, or siRNA) to selectively bind and inactivate specific gene sequences.

All human genes contain two copies of DNA, one inherited from each biological parent, that are ultimately translated into protein. Machado-Joseph and FTDP-17 are dominantly inherited diseases, meaning that a change in only one gene copy is sufficient to produce disease-causing mutated proteins. In these diseases, the normal gene copy often produces normal proteins that serve important functions in the body. Curing this type of disease would involve turning off only the mutant copy of the gene. Destroying both gene copies would prevent the normal proteins from being made, leading to potentially harmful side effects.

Earlier approaches to gene silencing could not distinguish between the good and bad gene copies, so the essential function of the normal gene copy was often lost. In the current study, the authors showed that RNA interference can successfully inhibit the mutant gene copy while letting the normal gene copy maintain its function. This approach worked even when the mutant and normal gene copies differed by only one molecule of DNA.

The authors found that some genes are easier than others to inhibit, but there seems to be no way to predict how well a particular form of siRNA will suppress a given gene. Through persistent attempts to modify the procedure, Paulson and his colleagues found a way to successfully block both of the neurodegeneration-associated genes.

With some genetic neurodegenerative disorders, particularly with the polyglutamine diseases, the mutation gets worse as the disease is passed down from generation to generation. This phenomenon (known as anticipation) causes the disease to be more severe and to begin earlier in children of affected patients. A treatment such as RNA interference might be the key to finding a cure for these fatal diseases.

Although the current study addresses two rare genetic disorders, “this approach might help other genetically similar diseases that have a clinically different appearance,” according to Katrina Gwinn-Hardy, M.D., a program director from the NINDS and an expert in the genetics of movement disorders. In fact, Dr. Paulson has recently published another study that showed gene silencing can be used to inactivate a mutant gene involved in dystonia, a common form of movement disorder.

“RNA interference is an elegant approach that can be used to specifically target not only problem genes in neurodegenerative diseases, but also genes expressed by viruses that can infect the brain,” says Dr. Paulson. He also speculated that even disorders such as stroke that do not have a specific genetic cause could one day be treated with this type of approach. For example, proteins that cause brain damage after stroke might be “knocked out” or suppressed by RNA interference therapy. “The critical question is that of delivery-what is the target, and how do we get the interfering molecules to that target,” Dr. Paulson suggests.

The next step in this field involves testing the RNA interference approach in animal models. Dr. Paulson is now collaborating with Beverly Davidson, Ph.D., also at the University of Iowa, to test this system using current gene delivery approaches in mouse models. “The ultimate goal is to cure or prevent disease with a one-time injection that will forever suppress the mutation in affected patients,” he says.

The NINDS, part of the National Institutes of Health within the U.S. Department of Health and Human Services, is the nation's leading supporter of research on the brain and nervous system.


*Miller, VM; Xia, H; Marrs, GL; Gouvion, CM; Lee, G; Davidson, BL; Paulson, HL “Allele-Specific Silencing of Dominant Disease Genes.” The Proceedings of the National Academy of Sciences, USA, June 2003, Vol. 100 (12), pp. 7195-7200.

- By Diane Lawrence, Ph.D.


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Last Modified April 16, 2014