# RNA interference/Medical

This page provides a non-technical exploration of the medical implications of the Nobel Prize in Physiology or Medicine for 2006, which was awarded to Andrew Fire and Craig Mello for their research on RNA interference.

## Medical uses of RNA interference

RNA interference might allow future treatments of human diseases such as Lou Gehrig's disease (amyotrophic lateral sclerosis, ALS).

### Trapped

Most people experience "sleep paralysis" at some point during their life. While sleeping, you might be aware of trying to move, but being unable to move. The frustrating and sometimes frightening experience of sleep paralysis can provide insight into the experience of living with advanced Lou Gehrig's disease. Most people with Lou Gehrig's disease retain their normal ability to think and reason while just the part of their nervous system that makes movement possible is selectively destroyed. What can go wrong to selective destroy the brain cells that control movement and leave people trapped in a body that will not respond to their wish to move?

### The medical strategy

In order to understand functional defects observed in Lou Gehrig's disease, the loss of movement control has been traced to specific organs, cell types and individual genes. What are the structural components of the nervous system that are specifically involved in control of movement? Up until the middle of the 19th century, diseased brain and spinal cord tissue could generally only be productively analyzed in terms of alterations in the gross anatomy. Although microscopy was then allowing advances in cellular pathology -the association of disease processes with structural changes in specific cell types of organs- the individual neurons of the brain and spinal cord were generally resistant to meaningful visualization by microscopy.
Anatomists such as Paul Broca were able to associate behavioral defects with structural damage to particular parts of the brain. The part of the brain called "Broca's area" was linked to disruption of speech generation without any block in the ability of patients to comprehend language. Broca's area is connected to nearby parts of the brain that contain cells with axons that carry movement control signals to the spinal cord. The bundles of movement control axons degenerate and are smaller than normal in patients with Lou Gehrig's disease.
About a decade after Broca's area was recognized as a movement control area of the brain, Vladimir Betz used a new technique, the Golgi stain, to identify a type of giant pyramidal shaped cells that are movement control cells of the brain. These "Betz cells" are among the largest neurons of the human brain and they are depleted from the brains of patients with Lou Gehrig's disease.
Lou Gehrig's disease is inherited in a genetically dominant way within some families. This pattern of inheritance allowed identification of a specific gene that is linked to the death of Betz cells in some families, the gene for an enzyme called superoxide dismutase. Superoxide dismutase can protect cells from molecular damage caused by oxygen. Normally oxygen is thought of as being required for human life, but the human body must also constantly protect itself from deleterious effects of highly chemically reactive oxygen molecules. Mutant forms of superoxide dismutase can lead to cell death.

### Treating Lou Gehrig's disease

Existing treatment options for Lou Gehrig's disease are very limited. Riluzole is a drug that inhibits the ability of some brain cells to generate the electrical signals that are sent down their axons. Clinical studies of patients with Lou Gehrig's disease have shown that some patients may live a few months longer if they are treated with Riluzole. Riluzole may have a beneficial effect by reducing damage to brain cells that naturally arises from their activity. Better treatments are needed that specifically target the causes of Lou Gehrig's disease.
The Nobel Prize-winning research on RNA inhibition might lead to new treatments for patients with Lou Gehrig's disease due to dominant mutations in the superoxide dismutase gene. Reduction in the level of the superoxide dismutase enzyme coded for by the mutant gene has been studied in animal models of Lou Gehrig's disease. Superoxide dismutase is a major protein in the brain and spinal cord, so it is a challenge to find ways to significantly reduce production of this protein in the movement control neurons. "RNA inhibition", often abbreviated "RNAi", is a normal process inside cells by which ribonucleic acid can lead to reduced levels of a specific protein. The specificity arises due to base-pair complementarity between the inhibitory RNA and target nucleic acids that are involved in producing a specific protein.
Since non-mutated superoxide dismutase might be beneficial, it would be useful to have a method that selectively decreases levels of the mutated form. Many dominant disease genes that cause Lou Gehrig's disease are point mutations. The RNA molecules that activate the RNA-mediated inhibition process are about 20 nucleotides in legth. It has been shown that highly selective RNA-mediated inhibition can be induced that selects between normal and point mutant superoxide dismutase.
Working with laboratory mice as an experimental model system for the human disease ALS, Miller et al showed that loss of muscle function could be slowed using RNA interference. This result was obtained by using a virus to induce RNA interference in neurons. Recent results indicate that disease-causing superoxide dismutase that is present in non-neuronal cells also contributes to the death of movement control cells and progression of the disease. These results from laboratory experiments suggest that if RNA-induced inhibition of mutant superoxide dismutase can be induced in the correct cells of the brain and spinal cord, it might be possible to slow progression of Lou Gehrig's disease in humans.