The AIDS virus is shrewd, agile, fast, and adept at evading the body's defenses. Can gene therapy put the killer to work?
Cell Genesys, a biotech start-up headquartered in Foster City, California, is one of several companies dedicating millions of dollars to getting HIV - one of today's most intractable biological evils - working for the good. Applying a technique that walks the line between brilliant and terrifying, company researchers are trying to hijack the hijackers by modifying the human immunodeficiency virus so that it unwittingly delivers disease-curing genes rather than its own deadly code.
Hemophilia, diabetes, cancer, and Alzheimer's disease are just a few examples of afflictions stemming from missing or mutated DNA. The nascent discipline of gene therapy aims to correct these genetic maladies by injecting healthy DNA into unhealthy cells, where it proceeds to multiply and reverse the damaging effects of a gene gone haywire.
Scientists trying to make gene therapy work have known that viruses implant their own DNA or RNA into the cells of the infected host; the invader genes commandeer the machinery of the cell to turn out copies of itself. Yet widespread use of gene therapy has been hindered not by technology, but, ironically, by our own bodies. The ultimate trick, say gene therapists, is to figure out how to get crucial genes into sick cells before the genes are attacked and destroyed by a patient's immune system. Few viruses can truly escape the body's line of defense long enough for gene therapy to take hold.
Cell Genesys may have solved that quandary with a new method of gene therapy that's both frightening and, at the same time, wonderfully clever.
Because HIV is a cunning virus that is particularly good at evading the body's defensive forces, scientists have realized that it could be the Trojan horse of gene therapy.
"The great advantage of working with HIV-1 is that we know so much about the molecular biology of the virus," says Luigi Naldini, a senior scientist at Cell Genesys.
Nevertheless, taming the virus is something like training a tiger to bring you the morning paper: You'll enjoy your coffee much more - and avoid becoming Tony's breakfast - if your pet has been declawed and muzzled. Using a technique first developed by Naldini and colleagues at the Salk Institute in San Diego, Cell Genesys researchers have succeeded in removing five of the virus's nine genes - those involved in viral replication.
With other gene therapies, the whole mechanism had to be meticulously tailored to avoid the body's defensive immune system - a mine field of watchdogs bred by eons of evolutionary time for the precise purpose of attacking and chewing up alien molecules. When HIV triggers AIDS it attacks T cells, our front-line immune defense. By deleting the virus's reproductive instructions, Cell Genesys researchers have created a mutated form of HIV that can no longer multiply or infect but is still capable of sneaking into T cells, carrying with it a therapeutic load of new genes.
HIV promises to skirt another problem that limited the success of early gene therapies: the blood-brain barrier. The blood vessels leading into the brain are narrow, so as to protect the brain from toxic material in the bloodstream, and they filter out most cells and large molecules. Unfortunately, this barrier also shields common disorders such as brain tumors and diseases like Parkinson's and Alzheimer's from potential gene therapies. HIV, however, can go where no virus has gone before, slipping into the brain - and into virtually all other cells in the human body - undetected.
Presumably, when the healthy cells divide to form two new cells, the introduced genes will replicate also, and thus continue their therapeutic function. And it's essential to introduce the good genes into the chromosome and get them to stick around long enough to get the job done. "The power of gene therapy lies in enabling the cells to produce small amounts of protein over a long period of time," says Frank Szoka, a gene therapy researcher at the University of California at San Francisco.
Cell Genesys and others are pioneering techniques that could keep introduced genes functioning for as long as a year, almost three times longer than previous methods. For diabetics, a gene would produce just the right amount of insulin whenever needed, eliminating the need for large-dose injections several times a day. A cancer patient's tumors would disappear as reengineered DNA - riding shotgun on HIV - reproduced itself to form new, healthy cells.
The FDA has implicitly given its blessing to Cell Genesys and a few better-known companies like Chiron and Merck that are working on similar gene-therapy methods. So far, the agency has approved more than 350 clinical trials, involving dozens of investigators and nearly 2,000 patients, for such conditions as cancer, cystic fibrosis, hemophilia, and Alzheimer's disease.
Though no real clinical successes have occurred to date, the research and medical communities sense that important breakthroughs are just around the corner. As University of Wisconsin geneticist Jon Wolff and Rockefeller University Nobel Laureate Joshua Lederberg have remarked, this new therapeutic approach combines the advantages of both pharmacology and surgery. Like pharmacology, it combats maladies with externally administered substances. And like surgery, it could alter a tissue or organ permanently.
Gene therapy is the next medical frontier - an entirely new branch of medicine that promises to revolutionize the way we treat human disease.
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