The small, windowless space at the Children's Hospital of Philadelphia looks like any eye doctor's examining room, with an adjustable chair and half a dozen machines for testing vision. The 20-year-old patient, however, has not come all the way from Albuquerque to get new glasses. Alisha Bacoccini, who has short, blond-streaked hair and green eyes, was born with a disorder caused by a malfunctioning gene in her retina cells that has been diminishing her sight since birth. Now she sees only pale and blurry shapes. "If I look at you I can't see eye color or acne or your eyebrows, but I can see that someone's there," she says. Her seeing eye dog, Tundra, a black Labrador retriever, sits at her feet.
A month earlier, in an experimental treatment, researchers injected Bacoccini's right eye—the worse one—with billions of working copies of the retinal cell gene. Now they'll find out if the treatment has worked.
Jean Bennett, a physician and molecular geneticist, has Bacoccini rest her forehead against a small white machine that flashes light into one eye, then the other. This pupillometer will indicate how well Bacoccini's eyes respond to light. "OK, one, two, three, open," Bennett says, and repeats the procedure 16 times. On a computer screen in the darkened room, Bacoccini's pupils are two giant black circles that contract ever so slightly with each pulse of light. Another researcher escorts Bacoccini to the next testing apparatus. Half an hour later, Bennett says: "I just looked at your pupillometry results. Good improvement."
"That's good," Bacoccini says, though she sounds unsure. Since a few days after the injection, she has indeed seen more light out of that eye, she says, but things seem blurrier. When she tries to read a giant eye chart with her right eye, she does no better than before—she can pick out only a few two-inch-high letters from 16 inches away. Then again, her eye is still red from the surgery. Bennett's husband, Albert Maguire, is the retinal surgeon who operated on Bacoccini. He peers into her eye and says the surface hasn't yet healed, adding: "Hopefully, that's all it is."
The prospect of using gene therapy to treat diseases—particularly inherited diseases that involve one errant gene, such as sickle cell anemia and cystic fibrosis—has tantalized scientists for decades. If there were some way to give a patient a good version of an implicated gene, the thinking goes, it might repair or prevent damage caused by the inherited bad one. This seemingly simple idea has turned out to be unexpectedly complex in practice. There have been hundreds of human gene-therapy trials for many diseases, from hemophilia to cancer, in the past 18 years. But nearly all failed because of the difficulties of getting a working gene into cells without also causing harmful side effects.
Until last year, gene therapy had worked unequivocally against only one disease, the rare affliction called severe combined immuno-deficiency (SCID), which is caused by a flaw in any of a number of genes needed to produce white blood cells. The disease leaves the immune system unable to fight infections and usually leads to death in childhood. It is also called "bubble boy" disease, after one famous patient, David Vetter, who lived to age 12 in a sterile plastic bubble. Since the mid-1990s, European researchers have cured about 30 kids with SCID by inserting the appropriate functioning gene into their bone marrow. But even this success has been mixed with tragedy: five of the children developed leukemia and one has died. In those patients, who had a particular variant of the disease, the therapeutic gene accidentally turned on a cancer-causing gene after merging with the patients' DNA. Researchers are now testing ways to make gene therapy for SCID safer.
U.S. gene-therapy research was set back substantially after 18-year-old Jesse Gelsinger, who suffered from an inherited liver disease, died of multiple organ failure in 1999 while participating in a gene-therapy experiment at the University of Pennsylvania. News of the death prompted an uproar in the scientific community and hearings in Congress, with the teenager's father, Paul Gelsinger, and others accusing the Penn researchers of being too hasty to test the treatment in people. According to the Food and Drug Administration, the researchers had not sufficiently warned Gelsinger and his family of the experiment's risks. The lead researcher had also failed to disclose that he had a financial stake in a company that stood to gain if the treatment succeeded. "Those were the terrible days. The field bottomed out," says Leon Rosenberg, a Princeton University human geneticist, who performed early lab studies on the liver disease that Gelsinger had. "The integrity of science was damaged tremendously."
Bennett and Maguire joined the Penn medical school faculty in 1992. One of their colleagues is James Wilson, who oversaw the study in which Gelsinger died. Wilson was subsequently barred by the FDA from conducting human experiments. But Bennett and Maguire were not involved in that study. Their experimental gene-therapy trial began in 2007 after years of review by federal regulators, the Children's Hospital and Penn committees set up to address ethical and safety concerns raised by Gelsinger's death.
Additional Sources
"Preliminary Results of Gene Therapy for Retinal Degeneration," Joan W. Miller, New England Journal of Medicine, May 22, 2008
"Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis," James. W.B. Bainbridge et al., New England Journal of Medicine, May 22, 2008
"Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis," Albert M. Maguire et al., New England Journal of Medicine, May 22, 2008
What a fascinating article. For an in-depth look at the many years of research and the many scientists that helped make LCA gene therapy a reality - the National Eye Institute (NEI) website has a good timeline at http://www.nei.nih.gov/lca/
Posted by Lee Tout on December 23,2008 | 04:21PM
I have a 17 year old granddaughter who was born with LCA. She attended Gov. Morehead School for the blind from age 4 years until she started junior high in the public school system. She reads braille and some limited large print. She is very intelligent and wants to be independent. Please advise me if there is some way she can be evaluated for trials in the gene therapy I have been reading about in your Smithsonian article. Any advice will be greatly appreciated.
Posted by John Hunter on January 4,2009 | 10:32AM
In reply to John Hunter:
Thanks for asking about how to find out more about gene therapy trials. The National Institutes of Health maintains a website, www.ClinicalTrials.gov, where you can search for clinical trials for various conditions. There are several LCA trials that appear to be recruiting now. The website shows which hospitals are participating in the trials and provides contact information. Best of luck to your granddaughter.
Posted by Laura Helmuth on January 5,2009 | 01:40PM
I was diagnosed with Juvenile macular degeneration at age 23.Now I'm 34 and I've prayed for a very long time for some sort of treatment for dry macular degeneration for more than ten years. This article on gene therapy brings hope for many people who are struggling and coming to terms with losing their central vision. Losing our vision is extremely painful and difficult. Coping with it and losing my independence brings tears to my eyes everytime. I can't see my toddler son or read to him. I teach but will soon have to leave my post because of this eye disease. Please keep me inform on any future treatments for dry macular degenation. Thank you from the bottom of my heart.
Posted by helen wong on January 6,2009 | 06:14PM
Great story and good news to bring this to the world. For more background about gene therapy and ongoing clinical trials, there is a comprehensive website at http://www.genetherapynet.com
Posted by Rik on January 8,2009 | 07:32AM
My 1 years old son is suffering from Stargardt's Macular Degeneration. This article on Genes Therapy gives hope to all us having Degeneration disease. Please let us know any treatment available for Stargardt's. Best Regards. God Bless You.
Posted by Muhammad on January 10,2009 | 03:28AM
I read your article and am very impressed with the work being done by Bennett and Maguire. I am a 55 year old male with RP in both eyes, my right eye is a lazy eye and my left eye is 20/60 and I'm at the point where I can barely function. Can I find out if there is any way that you can either give me their contact info or you could forward this to them. I would like to see them and perhaps, be a volunteer as well, I will meet them whenever. I would appreciate your help in this matter. Keep up the good work in informing those of us who have severe vision problems of the testing being done. I would appreciate your help. Thank you.
Posted by Raymond Jaar on January 11,2009 | 07:55AM
This article brings such hope! We have a 14-year-old daughter who suffers from severe myopia and cannot see more than 3 feet in front of her without wearing high prescriptive contacts or glasses. Her eyesight gets worse every year and we hope and pray that she can retain her vision because she loves to play basketball. Where can I find the best information for our daughter's condition. We have been to two ophthalmalogists and both have said there is nothing more to do than higher prescriptions for her and later laser surgery that may only temporarily fix her problem. We have been told she will always have the chance of retinal detachment and now is showing signs of astigmatism. Our daughter also has a friend who suffers from Stardgarts disease and I will pass along this article. Thank you.
Posted by Gina Armbrust on January 15,2009 | 09:21AM