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University of Iowa News

Nov. 11, 2005

UI Team Uses Gene Silencing To Correct Movement Disorder

Researchers at the University of Iowa Roy J. and Lucille A. Carver College of Medicine continue to advance a potential new treatment for neurological disorders. RNA interference, or RNAi, holds promise as a therapy for many diseases, including brain disorders, because it can selectively suppress or silence disease-causing genes.

In a new study published in the Nov. 9 issue of the Journal of Neuroscience, Pedro Gonzalez-Alegre, M.D., UI assistant professor of neurology, and his colleagues use RNAi to restore human neural cells to normal by selectively silencing a gene that causes the movement disorder DYT1 dystonia. The findings may also help researchers apply RNAi to other brain diseases such as Huntington's disease.

Starting in childhood, patients with DYT1 dystonia develop involuntary muscle contractions that cause twisting of limbs. The disease progresses over several years to involve the whole body and is very physically disabling, although patients have normal brain function. There currently is no cure and only limited treatment for DYT1 dystonia which, although rare, is the most common inherited dystonia.

The DYT1 mutation is the same for all patients with the disease. The mutation produces an abnormal version of a protein called torsinA. DYT1 also is a dominant disease, meaning that people with the disease have one normal torsinA gene and one mutated torsinA gene.

The function of normal torsinA is unknown, but it is critical because mice without the protein die within a day of birth. Abnormal torsinA acts in a toxic way and leads to the development of dystonia, but although the disease stops brain cells from working, it does not destroy the affected neurons.

"If RNA interference does turn out to be a good therapy for brain diseases, then DYT1 will be an especially good candidate because of the genetic and clinical characteristics of the disease," Gonzalez-Alegre said. "DYT1 is particularly attractive for RNAi because it is not a neurodegenerative disease -- there is no neuronal death. If you can correct the genetic problem you may be able to completely cure the disease."

For RNAi to be a feasible therapy it must clear several technical and safety hurdles. It must eliminate the toxic gene while leaving the normal gene alone; this is called allele specific silencing. It also must be deliverable to human brain cells, and it must not trigger potentially harmful immune reactions.

The UI study shows that for DYT1 in neurons, RNAi clears all these hurdles.

Gonzalez-Alegre and his colleagues found that in a human neural cell model of the disease, RNAi can specifically eliminate the toxic torsinA gene without affecting the normal gene. Importantly, the treatment appears to rescue the cells and return them to a normal state.

The UI team also proved that their delivery system, a viral vector called FIV, can be used to suppress torsinA protein in mammalian neurons, which means that the therapy should work in the brain cells that will be the target for treating DYT1 in humans.

Finally, the study also addressed the safety concern that RNAi might cause a potentially harmful immune reaction called the interferon response. This normal, defensive immune reaction is triggered by abnormal RNA and shuts down protein production in the cell.

"No one had previously looked at this in neurons and our study shows that therapeutic manipulation of RNAi does not trigger an interferon response in mice neurons or in rat neural cells. So it seems to be safe, at least from that point of view," Gonzalez-Alegre said.

Gonzalez-Alegre added that in addition to advancing RNAi as a therapy for DYT1, the findings should also be applicable to RNAi treatment of other more deadly brain diseases.

In addition to Gonzalez-Alegre, the UI research team included Henry Paulson, M.D., Ph.D., associate professor of neurology, Nicole Bode and Beverly Davidson, Ph.D., the Roy J. Carver Chair in Internal Medicine and UI professor of internal medicine, physiology and biophysics, and neurology.

The study was funded by the National Institute of Neurological Disorders and Stroke and the Dystonia Medical Research Foundation.

University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at

STORY SOURCE: University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178

CONTACT: Jennifer Brown, 319-335-9917