Gene therapy may provide a treatment for a group of incurable, progressive neurological diseases called polyglutamine-repeat diseases

Researchers from the University of Iowa have have shown for the first time that gene therapy delivered to the brains of living mice can prevent the physical symptoms and neurological damage caused by an inherited neurodegenerative disease that is similar to Huntington's disease (HD).

If the therapeutic approach can be extended to humans, it may provide a treatment for a group of incurable, progressive neurological diseases called polyglutamine-repeat diseases, which include HD and several spinocerebellar ataxias. The study, conducted by scientists at the UI Roy J. and Lucille A. Carver College of Medicine and colleagues at the University of Minnesota and the National Institutes of Health (NIH), appears in the August issue of Nature Medicine and in the journal's advanced online publication July 4.

"This is the first example of targeted gene silencing of a disease gene in the brains of live animals and it suggests that this approach may eventually be useful for human therapies," said senior study author Beverly Davidson, Ph.D., the Roy J. Carver Chair in Internal Medicine and UI professor of internal medicine, physiology and biophysics, and neurology. "We have had success in tissue culture, but translating those ideas to animal models of disease has been a barrier. We seem to have broken through that barrier."

Davidson and her colleagues used a viral vector (a stripped-down virus) to deliver small fragments of genetic material (RNA) to critical brain cells of mice with a disorder that mimics the human neurodegenerative disease spinocerebellar ataxia 1 (SCA1). The genetic material suppresses the disease-causing SCA1 gene in a process known as RNA interference.

Mice with the SCA1 gene that were treated with the gene therapy had normal movement and coordination. The gene therapy also protected brain cells from the destruction normally caused by the disease and prevented the build-up of protein clumps within the cells. In contrast, mice with the SCA1 disease gene that were not treated developed movement problems and lost brain cells in a manner similar to humans with this condition.

Both SCA1 and Huntington's disease are members of a group of neurodegenerative disorders caused by a particular type of genetic flaw. In these dominantly inherited diseases, a single mutated gene inherited from either parent produces a protein that is toxic to cells. Thus, a successful therapy must remove or suppress the disease-gene rather than simply add a corrected version.

"Although we know how to put genes into cells, the difficulty we face in treating dominant diseases is how to remove or silence genes," Davidson explained. "With our approach we can marry our gene therapy research using viral vectors with RNA interference."

Silencing the SCA1 gene with RNA interference inhibited the production of a neurotoxic protein, suggesting that this technology may also be helpful against other degenerative neurological diseases caused by neurotoxic proteins, such as Alzheimer's disease.

In addition to the finding that RNA interference inhibited gene expression to such an extent that it protected the animals against the disease, another important finding was that RNA interference in and of itself does not appear to be toxic to normal brain cells. In the UI study, neither animal behavior nor brain structures were adversely affected by RNA interference gene therapy.

Furthermore, the study revealed that specific properties of different gene therapy vectors can be used to target those cells that are most involved in causing the disease symptoms. In this case, the UI team proved that their gene therapy vector, adeno-associated virus 1, specifically targeted Purkinje cells, which are very important for gait and coordination.

"Choosing the right vector for the right cells could help us limit gene expression to those cells where altering expression will have a beneficial effect," Davidson explained.

Davidson is optimistic about the potential for using RNA interference gene therapy to treat neurological diseases like HD and spinocerebellar ataxias in humans.

"This is among the most important work I have done and I am excited about the prospect of helping to move this approach into clinical trials," she added.

In addition to Davidson, the team included UI researchers: Haibin Xia, Ph.D., and Qinwen Mao, Ph.D., who were co-lead authors of the study; Henry Paulson, M.D., Ph.D.; Steven Eliason; Scott Harper, Ph.D.; and Inês Martins. Harry Orr, Ph.D., at the University of Minnesota, and Linda Yang and Robert Kotin, Ph.D., at the NIH also were part of the team.

Davidson first presented these findings at the American Society of Gene Therapy meeting in May, where it was nominated the top abstract.