Researchers have demonstrated for the first time that physical symptoms and neurological damage caused by an inherited neurodegenerative disease that is similar to Huntingdon's disease (HD) may be prevented by gene therapy.
This therapeutic approach may provide a treatment for a group of incurable, progressive neurological diseases called polyglutamine-repeat diseases, which include HD and several spinocerebellar ataxias (loss of coordinated movement caused by disease of nervous system).
Beverly Davidson of the University of Iowa in the US, a professor of internal medicine and neurology and a lead investigator in the study, said:
"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,"
"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."
The results of the study are also significant because they show that it is feasible to deliver therapeutics based on the concept of RNA interference (RNAi) - a means of silencing the activity of genes - using a gene therapy approach.
The successful delivery method of the RNAi via a viral vector (a stripped-down virus) was used to deliver small interfering RNA (siRNA) fragments to critical brain cells of mice with a disorder that mimics the human neurodegenerative disease spinocerebellar ataxia 1 (SCA1). The siRNA material was designed to bind to and suppress the disease-causing SCA1 gene.
Mice with the SCA1 gene that were treated with the gene therapy had normal movement and coordination and their brain cells were protected from destruction. The active treatment also prevented the build up of protein clumps within the cells, a marker for cellular dysfunction.
Meanwhile, SCA1 mice that were not treated developed movement problems and lost brain cells in a manner similar to humans with this condition.
Both SCA1 and Huntingdon's are inherited diseases caused by a particular type of genetic flaw in which a single mutated gene inherited from either parent produces a protein that is toxic to cells. Any successful therapy must remove or suppress the disease-gene as opposed to simply adding a corrected version.
Davidson explained. "With our approach we can marry our gene therapy research using viral vectors with RNA interference."
"Although we know how to put genes into cells, the difficulty we face in treating dominant diseases is how to remove or silence genes."
Inhibiting the SCA1 gene with RNA interference causing the non-production of a neurotoxic protein provides the foundation for a treatment against other neurological degenerative diseases caused by neurotoxic proteins, such as Alzheimer's disease.
An additional finding by the researchers was that RNA interference in and of itself does not appear to be toxic to normal brain cells. The study demonstrated that neither animal behaviour nor brain structures were affected by RNA interference gene therapy.
Davidson said: "As yet, we have noted no unwanted side effects. RNAi in normal mice was not detrimental, it did not induce behavioural or morphological problems using the assays described in the paper."
The study additionally revealed the specific vectors used to target those cells that are most involved in causing the disease symptoms. The vector used in this study, specifically targeted Purkinje cells, essential for movement and coordination.
Davidson explained: "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."
"This viral vector is currently being used for human brain disease therapy and we and others are investigating lentivirus vectors also."
Davidson told DrugResearcher.com that currently there was no date set for human trials as the research was only at a basic research stage. However they were looking toward initiating studies in larger mammals.
Currently there is no cure for Huntington's disease and treatment options are generally aimed at controlling symptoms. Antidepressants such as fluoxetine (Eli Lilly's Prozac) can be helpful with depression, and mood stabilisers and antipsychotic drugs can help with some of the emotional disturbances.
In addition, Aventis' Rilutek (riluzole) is a compound that diminishes the glutamatergic signals sent between brain cells, already approved for the treatment of motor neuron disease. Since glutamate excitotoxicity is believed to contribute to HD pathogenesis, it seemed a strong candidate for therapeutic treatment of HD.
Early studies have demonstrated that HD patients tolerated riluzole well and some decreases in the uncoordinated movements characteristic of the disease were seen.
The study, which was conducted by scientists at the UI Roy and Lucille 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 4 July.