Q -
What does the recently published study in Nature Medicine using RNAi mean for HD? And is RNAi therapy for HD around the corner? These are questions on the mind of those who have HD, are at risk for HD, or care for those with HD.
A -
What is RNAi?
RNAi is a naturally occurring biological process that takes place in all kinds of creatures, from plants to humans. It is a process by which cells can regulate the expression of specific genes at the RNA level. For the expression of some genes during development, regulation by RNAi occurs naturally. But scientists have now taken advantage of this machinery to introduce RNAi molecules into cells to silence the expression of specific disease genes. The recently published work by Davidson and colleagues at Iowa uses RNAi to silence expression of the disease gene in spinocerebellar ataxia type 1 (SCA1), which has important similarities to HD. This is why the studies are relevant to HD.
We should start with a little background. All our genes are made of DNA, consisting of two complementary strands twisted into the double helix made famous by Watson and Crick. Many genes code for proteins -- for example the HD gene codes for the protein, huntingtin. In order for a cell to make huntingtin, the HD gene is transcribed into RNA - literally, a precise RNA copy is made of one strand of the DNA. This single-stranded RNA, called a messenger RNA or mRNA, leaves the nucleus and enters the cytoplasm of the cell. In the cytoplasm, the cell's protein-producing machinery, known as the ribosome, "reads" the mRNA and builds a protein based on the blueprint provided by the mRNA.
In a nutshell, mRNA is the necessary intermediary, or messenger, that allows huntingtin and other proteins are made. If mRNA is not made from the HD gene, or if the mRNA is rapidly destroyed, then huntingtin protein cannot be made.
Because in HD and in many related neurological diseases, the disease protein is the bad actor, eliminating its production makes sense. By exploiting RNAi to destroy the mRNA -- essentially "shooting the messenger" -- scientists can prevent the production of a specific protein.
In the recent NM study, Davidson and colleagues used RNAi to prevent production of ataxin-1, the disease protein in spinocerebellar ataxia type 1. Much like mutant huntingtin, ataxin-1 has the abnormal expanded polyglutamine stretch that causes brain cells to degenerate.
What do the recently published studies using RNAi mean for HD?
What is exciting about the SCA1 study is that RNAi was successfully delivered to the brain of transgenic mice to essentially halt the disease. Essentially, a form of gene therapy was used. The Iowa scientists engineered a virus to express RNAi against the SCA1 gene. When the virus was injected into the cerebellum of SCA1 mice, the brain cells which took up the virus produced RNAi against the SCA1 gene. As a result, the disease protein ataxin-1 was no longer produced and the mice did much, much better than SCA1 mice that did not receive the RNAi virus.
It is important to note that normal mice injected with this virus showed no ill effects. This suggests that viral-mediated RNAi can work well and safely in mammalian brain - at least in mice and hopefully in humans. A second important point is that the cerebellum was targeted in SCA1 mice. The cerebellum is not a major target in HD. As everybody knows, the striatum and cerebral cortex are the major targets in HD. Whether RNAi will work as well and as safely in the striatum and cortex is something to which we may soon know the answer.
And is RNAi therapy around the corner for HD?
For mice, maybe. For humans, no. It takes a long time to bring an experimental therapy like this to human trials. Remember, the approach used was a gene therapy approach, which has had its share of problems and disappointments in the past 10 years. Fortunately many of the best and brightest scientists are still working on ways to get robust, safe and sustained expression of gene therapy in the brain. And while RNAi is a hot topic right now with real promise, there is still much more to be learned about its delivery, safety, sustainability and specificity before we can move this forward into people. To apply the strategy used in the Nature Medicine study to humans would require neurosurgery -- injections of the engineered virus into the brain. Companies are also working on nonviral ways to deliver effective RNAi.
So in summary, while this study is exciting indeed, RNAi therapy is not something we can absolutely count on. We need to keep looking for other approaches to treat HD. A sign of hope is the great many articles published in the past year pointing to other potential therapies for HD. We must keep up the pressure on all these fronts.
|
