A Gene Disconnect
Two Packard studies are on track for silencing a familial ALS gene.

If you could slightly adjust the DNA of patients with familial ALS who suffer from a mutation of the SOD1 gene—and do it safely and effectively—most believe there’d be a cure. Of course, operating within a cell nucleus with a diameter roughly a ten-thousandth of a pencil lead is out of the question. Recently, however, two methods have surfaced that offer the molecular equivalent of DNA surgery.

“With so much unknown about how mutated SOD1 genes lead to disease, the most rational approach to familial ALS is to focus on what we know goes wrong,” says Center cell biologist Zuoshang Xu, “and try to block it.” That means damping the gene’s activity early on. Now, after early work in that direction, both Xu, at the University of Massachusetts, and Packard biochemist Don Cleveland at the University of California, San Diego, are optimistic.

Cleveland’s work is the farthest along.* His approach, called “antisense,” targets the SOD1 gene’s ability to transfer its flawed message to the body of the cell. Antisense agents render that process vulnerable to enzyme attack. In effect, they shut the gene down.

So far, Cleveland has tested antisense in SOD1 rat models of human familial ALS and blocked roughly half of the mutant gene’s activity—enough to let the animals live significantly longer. His first studies have targeted SOD1's most common flaw. “We’ve shown antisense can be effective against the human A4V mutation, the most prominent in North America,” he says. “The type of ALS it produces is also one of the most drastic. Patients typically die in a year or less.”

Because flawed gene activity isn’t a one-time thing, Cleveland’s group and their biotech firm collaborators have figured out how to bathe the spinal cord continually with the antisense agent. A refillable pump beneath the skin sends antisense to the brain, where it feeds into spinal fluid. “The rat models have robustly shown us you can silence the SOD1 gene that carries errors,” says Cleveland. Now his group plans more sophisticated tests with primates, the sort that would pave the way for a clinical trial. “We’re hoping for a patient study next year.”

Xu’s studies of a newer technique called RNA interference (RNAi) may offer a more complete block of a variety of mutant SOD1 genes. RNAi’s currently under study for Parkinson’s disease and cancer.

Like antisense, RNAi gums up the way a specific gene’s message gets out, though at a slightly different point in the process. It, too, can be administered using a small pump under the skin. Unfortunately, RNAi sometimes quiets useful normal SOD1 genes along with the abnormal ones that exist in animal models and human patients. “Knocking out normal genes,” Xu says, “could cause problems including increased sensitivity and nervous system injury.” So, along with the complete block, Xu’s team also introduces normal genes. Fortunately, because of a trick of engineering, RNAi can’t silence them.

So far, the techniques both shut off abnormal SOD1 in cell cultures and let normal genes work, Xu says. Next, he says, come more difficult studies in animals. “They’re simple in principle,” he says. “Now we’ll see what happens in practice.”

*This work is funded by ALSA and the biotech firm Isis.

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