July 27, 2006

Research Update — from ALSA’s National Office

Antisense Treatment Prolongs Survival in ALS Rats

Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator

Researchers led by Don Cleveland, Ph.D., have published in the Journal of Clinical Investigation that a treatment aimed at a mutant protein linked to some inherited forms of amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) prolongs life in rats that show many features of the disease. The approach, called antisense, is planned for clinical testing in ALS patients in 2007.

By delivering the drug directly to the cerebral spinal fluid that circulates inside the brain, investigators were able to lower production of the mutant protein in neurons and surrounding cells. Similar results were obtained in both small and large laboratory animals.  In certain rats that experience many aspects of ALS, the antisense treatment also extended the animals’ lifespan.

The researchers are paving the way to a therapeutic approach for ALS that delivers an antisense drug to the specific cells that are reacting to the toxicity of the defective protein. Antisense inhibits production of that targeted protein. Investigators plan to deliver the antisense drug made by Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) directly into the fluid around the spinal cord using pump technology already demonstrated as safe for people.

The investigators at the Ludwig Institute of the University of California, San Diego, funded by The ALS Association, showed that rats respond to the antisense therapy by producing far less of the targeted protein. The antisense drug effectively inhibits the expression of the gene that codes for the protein copper-zinc superoxide dismutase (SOD1) that is mutated in some inherited forms of ALS and initially introduced into the rats by genetic engineering to create a model for disease research. The rats are bred to continue to carry and express this mutant human gene.

These rats usually show signs remarkably similar to human ALS and die at about four months of age (rats usually live for a year to eighteen months). Rats treated with antisense targeting SOD1 given directly and continuously into the brain by a tiny pump under the skin, beginning before the symptoms started, survived the disease period by about a third longer than the rats given a placebo. This longer survival during the symptomatic period of their disease was evident despite the artificially large amounts of mutant SOD1 produced by these transgenic rats.

Clinical testing in ALS would most likely recruit patients with the gene change in SOD1 called A4V responsible for about half of the SOD1 mutations in North America. This gene change produces an especially aggressive form of the disease with death typically within a year of diagnosis.

The investigators noted in their report that if the antisense approach works for ALS, it would provide proof of principle for various other neurodegenerative conditions that also might be amenable to this strategy, including Alzheimer’s disease.

For further information about antisense technology as applied to ALS, click here.