Why the New Antisense Trials Make Sense for ALS

This February, a new entry in the ALS clinical trials system will have top scientists watching intently for results. It’s the start of human tests of a therapy based on a totally new principle—one that works by silencing mutant genes.

The effect should be like taping the genes over with Velcro so their destructive message can’t carry over into key nervous system cells.

“Gene inactivation is a new area of therapeutics,” says Packard Director, Jeff Rothstein. “We have no idea what failure rates are like. Success could be high or low. Since it’s unlike anything we’ve tried in ALS, we just won’t know until we do it.”

The new approach targets the mutant SOD1 gene that causes ALS in the most common familial form of the disease. SOD1 errors account for about a fifth of familial patients. (The mutations trigger roughly 3 percent of the total ALS worldwide.) And it’s having a known disease gene that gives this technique hope.

So far, blocking SOD1 has delayed the onset of disease in the mutant mice and rats that model ALS. And tests with higher animals—primates—show the drug does indeed affect target genes properly. “So it made sense,” Rothstein adds, “to try to translate this into human therapy.”

With the technique—researchers call it antisense—small molecules are introduced into the nervous system that are exquisitely tailored to bind to the DNA that makes up the SOD1 gene. The effect really is like Velcro, blocking the gene and preventing its usual way of expressing its message in cells. As the technique now stands, it cannot silence all of the mutant gene activity; it just lowers it. The animal tests show, however, that complete silence may not be necessary.

The upcoming trial, sponsored by ISIS Pharmaceuticals, Inc., is a Phase I trial, which means it tests for safety only. That’s why it’s small, with ultimately 32 subjects. The design was set up under the considerable expertise of the Northeast ALS Consortium, a chain of academic testing centers that includes Packard scientists.

The study starts with only a handful of patients, then will bring in more if side effects are slight or absent. It takes place at six trial centers nationwide, including the Johns Hopkins Comprehensive ALS Clinic with ties to the Packard Center.

Considerable science lies behind this use of antisense for ALS. Packard’s Rothstein and Robert Brown with the University of Massachusetts first blocked SOD1 genes using antisense methods in 1995 as a way to understand how the mutant gene caused disease. More recently, Packard scientist Don Cleveland, UCSD, and Tim Miller at Washington University began looking at antisense as a possible therapy, starting with mouse models.

“ISIS stepped in as the driving force,” Rothstein explained. The pharmaceutical company, which specializes in antisense technology, has developed antisense drugs—they are farther along in the clinical trials pipeline—for cancer, cardiovascular disease and other illnesses. Their biochemists engineered a form of antisense for ALS that stays in the body some four weeks.

“We still have major questions that need to be answered,” says Rothstein. Can we deliver antisense to the right tissues? How will we measure if it truly lowers mutant gene activity? How much gene-blocking do you need? Will it stay safe long-term? And, ultimately, can it work to slow down disease if patients already have obvious weakness?

“We know mice and rats can do pretty well without any SOD1,” he adds. Will humans do the same if the activity of both their healthy SOD1 and mutant SOD1 genes is lowered? And even though the Phase I test is for safety, will it give any evidence that the approach is working?

“That’s why we’re starting these tests,” says Rothstein.

The research was supported by the National Institute of Neurological Disorders and Stroke, the Roman Reed Spinal Cord Injury Research Fund, and The California Institute for Regenerative Medicine.