Gene Therapy's Unsteady First Steps

[mk99]

Gene Therapy's Unsteady First Steps
Initial experiments have led to both positive and disturbing results, forcing scientists to temper, but hardly abandon, their expectations

On Oct. 11, researchers at Jefferson Medical College in Philadelphia announced that they had reversed the progression of Parkinson's disease in rats. They had achieved this breakthrough by means of gene therapy -- using a harmless virus to replace Parkinson-causing genes in rat brains with good genes that effected a repair.

The Parkinson's discovery was overshadowed by another announcement, however. In Gaithersburg, Md., scientists had found proof that a French toddler developed a leukemia-like condition as a result of gene therapies that had mutated his DNA in unintended ways. A 17-member U.S. Food & Drug Administration scientific committee decided to halt any similar experiments in the U.S. for kids with this ailment, adenosine deaminase (ADA) deficiency. This rare genetic disease -- commonly known as Boy-in-the-Bubble Syndrome -- leaves children prone to repeated infections.

"VERY EARLY STAGES." The FDA committee expressed optimism that other gene-therapy trials would prove successful. Nevertheless, the bad press was reminiscent of a 1999 case in which a 19-year-old man died from an adverse immune reaction to gene-therapy treatment he was receiving at the University of Pennsylvania in Philadelphia.

These seemingly contradictory developments sum up researchers' attempts to advance medicine by extraordinary means -- ranging from monkeying with genes to cloning entire beings. The promise of such work is huge, but so are the uncertainties. "Regenerative medicine is at the very early stages," says Barrie Carter, the chief scientific officer of Seattle drug company Targeted Genetics.

Certainly, expectations for cloning and gene therapy have become more modest over the past few years. In 1997, the appearance of Dolly the cloned sheep had pundits predicting a world full of cloned animals and genetically improved humans. More cautious scientists imagined medical treatments based on cloned organs, a process dubbed "xenotransplantation." Even the least ambitious saw Dolly as proof positive of gene therapy's promise to cure such disorders as cystic fibrosis and muscular dystrophy.

DOLLY FOLLY. It's obvious now that such great expectations were premature. After burning through millions in research dollars, the Scottish company that cloned Dolly, PPL Therapeutics, put much of its genetic research up for sale in September. That same month, researchers at the Massachusetts Institute of Technology published a paper detailing disturbingly high gene-mutation rates in cloned animals. "When you age cloned mice, they all die early with severe problems in many tissues," says Rudolph Jaenisch, an MIT biology professor who coauthored the paper. "When we look at gene expression in newborne clones, every clone has major mutations."

Now even the big guns in biotech are narrowing their sights, focusing first on gene therapy. Witness the $4 million private equity placement that biotech pharmaceutical giant Biogen (BGEN ) gave Targeted Genetics (TGEN ) on Oct. 8. The payment to the Seattle outfit was, in part, a reward for successful indications during the Phase II FDA trials of Targeted Genetic's new cystic fibrosis gene therapy.

"It looks like we're close to proving that we can put a gene into the lung of cystic fibrosis patients and positively affect their lung functions," says Carter. One reason may be that scientists are becoming much more adept at successfully injecting DNA into living cells to correct their genetic weaknesses. Targeted Genetics has an entire battery of methods.

REWIRING THE BRAIN. Carter concedes that with gene-therapy research still in its infancy, adverse side effects might not show up for years or might be hard to track. Yet most major advances in medicine come about in fits and starts. The 10 other children in the French gene trial -- all of whom suffer from Boy-in-the-Bubble Syndrome -- have enjoyed measurable improvements in their lives.

"The therapy completely rebuilt their immune systems," says Carter. Moreover, the Jefferson Medical College experiments raise the prospect that gene therapy, more than simply replacing a missing or mutated gene, can rewire the brain's circuitry. Meanwhile, researchers are pressing ahead with human gene-therapy trials on everything from Parkinson's to cardiac diseases to various forms of cancer to AIDS -- and none are reporting major complications from the gene therapy.

The lesson seems to be proceed with caution, but by all means, proceed.


By Alex Salkever, Technology editor for BusinessWeek Online