FROM:
Nature Medicine 10, 1267 (2004)
New technologies deliver in treating neurological diseases
Emily Singer
San Diego
RNA interference, osmotic pumps may solve drug delivery problems.
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.
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."
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