New techniques that use RNA interference (RNAi) and osmotic pumps to deliver medicines are moving to clinical trials after proving successful in animal models of amyotrophic lateral sclerosis (ALS). If the methods are successful in humans, researchers say, the results may be applicable to other neurological disorders.

Delivering therapies to the cells that need them is a daunting obstacle in treating neurodegenerative diseases, such as Parkinson disease and Huntington disease. Researchers have had some success in animal models, but none of the therapies have yet proven effective in people. Some researchers say that may be because the medicines did not reach the target cells at high enough concentrations.

“We know we have effective concepts, but we need to deliver them to the cells at risk,” says Don Cleveland, a neuroscientist at the University of California in San Diego.

We know we have effective concepts [for treatment], but we need to deliver them to the cells at risk. Don Cleveland, University of California in San Diego

ALS is a fatal degeneration of the nerve cells that control muscles. In most cases, the root cause is unknown, but about five percent of cases are inherited. Familial ALS—often related to a genetic defect in the antioxidizing enzyme SOD1—is usually fatal within nine months. “It makes sense for ALS to be the proof of principle because the prognosis is so fast and so well defined,” says Cleveland. He and others presented their work at the Society for Neuroscience annual meeting in November.

Targeting treatment to the brain is difficult because the blood-brain barrier blocks many drugs. Gene therapy can bypass the barrier with viruses engineered to carry signals marking them for transport into nerve or muscle cells. Osmotic pumps implanted into ventricles—fluid-filled cavities in the brain—can deliver medicine directly to the cerebrospinal fluid, where it is ultimately taken up into neurons.

In RNAi, small fragments of double-stranded RNA bind to the target RNA sequence, preventing it from producing protein. A Swiss team used the technique to silence defective copies of the SOD1 gene using a carrier that can bypass the blood-brain barrier. To restore function, they also built a normal copy of the gene into the vector. The method improves muscle function in a mouse model of ALS, says lead researcher Patrick Aebischer.

Another approach is to deliver gene silencers directly into the ventricles. In a technique similar to RNAi, Cleveland's team used an osmotic pump to deliver short sequences of DNA that bind to the SOD1 RNA and target its destruction. Unlike RNAi delivered by viruses, however, the pump can be stopped if necessary, assuaging concerns about gene therapy in the brain. The technique can effectively silence the gene encoding SOD1 in rats and is being tested in skin cells from a patient with familial ALS.

It's too soon to predict how effectively the pump will deliver therapy through the length of the human spinal cord, but the medicine should reach the target neurons and delay disease progression, Cleveland says.

The benefits of gene silencing will be limited to diseases with known genetic mutations, notes Jeffrey Rothstein, a researcher at Johns Hopkins University. “But the therapy could have enormous impact for people who only have nine months to live,” he says.

Scientists are testing more broadly applicable techniques to deliver growth factors to ailing cells. A pump system is also being tested in a few Parkinson disease patients.

Scaling up therapy from rodents to humans has been notoriously difficult, says Cleveland, but “one of these techniques has a real chance of being effective.”