The Gatekeeper 

What if scientists devised a strategy to tackle some of the world's most notorious diseases, but just one company held all the patents?

Page 3 of 6

Sangamo's solution is to slow the nerve damage by stimulating production of a natural nerve-protecting agent. In the current clinical trial, patients are injected in the legs with a solution that is absorbed into their muscle cells. The zinc fingers turn on the gene that makes the needed nerve protectant. Nobody is sure how often dosing would need to be repeated — right now they're testing injections every two months — but it would certainly be less frequent than dosing for antidepressants and painkillers, which need to be taken daily.

Sangamo also is looking into using zinc fingers to activate the gene that makes a neural growth factor that may improve motor function in Parkinson's patients. Genes can be turned off for therapeutic effect as well; Sangamo is investigating gene repression as a way to modulate nerve pain.

In addition to turning genes on and off, zinc fingers can be used to modify or replace them. The most compelling test case Sangamo has for this approach is HIV. Some people are born with a natural resistance to the virus — even if you put their immune cells in a Petri dish and bombarded them with HIV, they still wouldn't become infected. To infect a cell, the virus must bind to a site on it called the CCR5 receptor, and people with natural immunity are missing one or both copies of the corresponding CCR5 gene. People totally lacking the gene never become HIV positive; people with one copy can become infected, but their progression to full-blown AIDS is dramatically slowed because the virus cannot easily spread through their bodies and bind to other cells. (One intriguing, although disputed, theory is that people with this HIV-resistant blood are descended from survivors of Europe's bubonic plague, which also may have spared people without this gene.)

Since it seems people are not harmed by lacking this gene, and in fact are better off without it, pharmaceutical companies have tried with varying degrees of success to develop drugs that would block these CCR5 receptors and keep the virus from entering. But Sangamo's approach is to disable or "delete" the gene altogether. Zinc fingers could bring in enzymes that slice the DNA apart, activating a natural, albeit error-prone, resealing process.

Think of the DNA sequence as a cassette tape with a recorded message, Wolffe says. Now imagine that you've cut a section out of the tape, spliced the ends back together, and tried to play it again. "All of the sudden you've got a blip in the middle of it," she says. "You can't actually hear what all was said — you're missing a word or two." With this DNA message disrupted, the cell no longer has the code for CCR5 receptors — and there's nothing left for HIV to bind to.

Eventually, the company hopes to harness this mechanism as a vaccine for people without HIV. But initially, Gregory said, this kind of therapy would be an intensive process for HIV-positive patients, in which T-cells would be removed, treated outside of the body, and then returned to the bloodstream. "What it would do is limit viral load and it would also prevent opportunistic infection," Gregory said. Sangamo expects to start human clinical trials for this therapy later this year.

While possibilities suggested by the HIV and diabetes examples are profound, Sangamo execs are quick to point out the limitations of zinc fingers. They're best used for conditions in which treating a small amount of tissue can provoke a profound therapeutic effect, not diseases involving huge numbers of cells all over the body, like metastatic cancer. At this stage, they're also limited to treating so-called monogenic diseases — those caused by one malfunctioning gene, rather than the interplay of several. Since trials in people have been small-scale, there is still much to learn about how well these therapies will be received by the body, how long they might produce positive effects, and if there will be any surprise complications.

Nobody yet knows how much such therapies will cost if they do eventually come to market, or how available they will be to the world's poorest citizens, who are disproportionately affected by diseases like HIV. Then again, muses Friedman, "What else is new? New technologies are never distributed in what you and I might think of as an equitable or fair way, where the distribution is directed at those who need it most. Sadly, that is not the way our world spins."

Concerns about boundaries and ethical use have been leveled at the entire field of gene modification. As genetic manipulation gets more accurate and market demand pushes biotech companies to provide a wider and wider variety of applications for the technology, Sangamo, by virtue of being a principle patent holder, will influence how that research progresses.

So far, most researchers looking into human genetic modification have been looking for therapies for serious diseases, most of which have no other cure. But like any other method of gene transfer, zinc finger technology could theoretically be used to modify any gene, and that leaves the door open to enhancement — modifying the human genome to make a person, say, more athletic. As Jesse Reynolds from the Center for Genetics and Society points out, the line between what is medical therapy and what is enhancement, or between what is a disability and what is just a difference, can get blurry. "To pick at one gray area, is obesity a disease?" he asks. How about dwarfism or deafness or male pattern baldness — if we had a choice, should we try to eliminate them? Watchdogs worry that biotech companies will follow the lead of the pharmaceutical and surgical industries, which have medicalized many complaints that would have once been considered cosmetic. (Think your breasts are too small? You have micromastia! Not happy in the bedroom? Try Viagra!)


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