From Tomatoes to fALS: Will Antisense Make Sense?

Not long ago, agricultural scientists thought that a tomato that could both ship well and burst into full ripeness in the grocery store was a vegetable-lover’s hallucination. But then came a way to turn down the early activity of a single gene for ripening—a technique called antisense—and Flavr Savr tomatoes have become a supermarket staple.

The groundwork for the trials was laid by Packard scientist Don Cleveland and his colleagues Tim Miller and Richard Smith. All three are with the University of California at San Diego.

Cleveland’s animal studies gave antisense the green light

“Not long ago, the FDA approved one use of antisense, a drug to treat a viral eye infection,” says Center Director Jeffrey Rothstein. “That, plus what we’ve seen in preclinical (animal) studies of the technique, certainly encourage further testing.”

At the most basic level, antisense works on a cell’s protein-making process, one that begins with genes and ends with proteins. Normally, a gene’s-worth of DNA passes protein-making instructions out to the body of the cell, where protein assembly occurs. The go-between molecule, messenger RNA (mRNA), carries the “sense” of those instructions to the assembly site. But scientists can engineer artificial bits of RNA—called antisense oligonucleotides—which slip into cells. Attracted to mRNA, the added antisense RNA binds to it, making it unavailable for message-transferring. In a gross way, it’s like covering Braille with duct tape.

In the current studies, instructions from the SOD1 gene, the one linked to ALS in many familial patients, becomes antisense’s target. Some 100 different mutations in that gene have surfaced. “But because developing an antisense drug for each mutation is probably not practical,” explains Miller, “we try to silence all SOD1 genes, mutant or normal.” Blocking normal SOD1 shouldn’t be a problem, the scientists say, because antisense is rarely 100 percent effective. Some SOD1 action would still exist. In Cleveland’s preliminary studies with rats and monkeys, the antisense drug had acceptable side effects.

More safety studies and FDA approval remain before small, human pilot trials can begin, Miller says. “Because such a trial is designed to test the approach’s safety, it probably uses too few patients—only 16—to measure any slowing of disease,” he explains, “but we’re open to the possibility.”

Next > Buoyed by Boye’s Gift
“It’s the purest type of philanthropy—giving to someone you trust.”