Points of Light in Gene Therapy Renaissance

Points of Light in Gene Therapy Renaissance

By Ricki Lewis

Patient success stories drive gene therapy forward.

July 29, 2010 | WASHINGTON, DC—Like the mythical Phoenix that springs anew from its ashes, gene therapy shows signs of re-emerging with a stockpile of safer and more efficient viral vectors. At the annual meeting of the American Society of Gene and Cell Therapy last May*, optimism was palpable.

The excitement peaked when 9-year old Corey Haas walked onstage at the Presidential symposium. His physician, Jean Bennett, professor at the F. M. Kirby Center for Molecular Ophthalmology at the University of Pennsylvania, announced: “I’d like to introduce the youngest person ever to speak at ASGCT.”

Until his gene therapy in September 2008, Corey was headed for blindness from Leber congenital amaurosis type 2 (LCA2). Today he plays baseball and just recently saw fireflies for the first time. He calmly answered questions from an astonished audience, and afterwards was mobbed by awed scientists, some in tears.

Earlier that day, Corey and his parents joined other emissaries of recent advances in gene therapy at a news conference. It was sparsely attended because across town, Craig Venter had just announced that he had artificially created life.

LCA2 is caused by mutation in the RPE65 gene. “RPE65 helps to recharge vitamin A, and without it, there is no vision. The gene therapy idea was simple—deliver the gene to the retinal pigment epithelium,” which hugs the photoreceptors, said Bennett. The pediatric clinical trial at Children’s Hospital of Philadelphia treated 12 patients between the ages of 8 and 24 in one eye. All improved.

The target disease most like the metaphorical phoenix is severe combined immune deficiency (SCID). Gene therapies for two treated forms had problems. First was ADA deficiency, tried on a 4-year-old in 1990. Her restored health could have been due to concomitant enzyme replacement. And gene therapy for SCID-X1 (“bubble boy disease”) worked, but caused leukemia.

Don Kohn, director of the University of California Los Angeles human gene medicine program, discussed new gene therapy trials for both forms of SCID using safer vectors. A trial to treat 20 boys with SCID-X1 is underway in Paris, London, and three sites in the U.S., using a “self-inactivating” retroviral vector. And for ADA deficiency, Kohn’s group is using the chemotherapeutic busulfan to clear space in the bone marrow for replacement cells, and using a lentivirus (HIV), which works in non-dividing cells, carries bigger genetic payloads, and integrates more efficiently than past vectors. “To date, four of eight patients have benefited clinically, living at home and doing well,” he said. And that’s without enzyme replacement.

In the second row at the press conference sat three young women who catalyzed gene therapy for their family’s disease, adrenoleukodystrophy (ALD), the genetic disorder portrayed in the film Lorenzo’s Oil. When Nathalie Cartier-Lacave arrived, the four women embraced. Cartier-Lacave is director of research at INSERM in Paris.

The ALD protein normally admits very long chain fatty acids into peroxisomes, where they are degraded and used to make myelin, which insulates neurons. Behavioral symptoms rapidly progress to seizures, blindness, and incapacitation. “The only treatment, a stem cell transplant, takes 12 to 18 months for progression to stop,” said Cartier-Lacave, but is risky. Gene therapy, also using HIV, exploits the fact that the brain cells affected in ALD (the microglia) come from bone marrow. The first two patients made headlines in fall 2009, after they had been making normal ALD protein for many months, as MRIs tracked remyelination. “There was no problem with HIV or immunity or insertion into a gene that causes leukemia,” said Cartier-Lacave.

Eve (Salzman) Lapin said that after her son Oliver was diagnosed with ALD in 2000, genetic testing found that one brother and a cousin had also inherited the disorder. Sisters Amber Salzman (an executive at GlaxoSmithKline at the time) and Rachel Salzman (a veterinarian) launched Stop-ALD, uniting researchers for a clinical trial. “They did everything shy of following us into the men’s room,” jokes Jim Wilson, professor of pathology and laboratory medicine at the University of Pennsylvania, who helped the sisters.

Lapin had the final word at the news conference. “The legacy of Oliver’s life and death is that gene therapy will be a better way to treat ALD and other terrible diseases.”

Ricki Lewis is the author of The Forever Fix: The Rise, Fall and Rebirth of Gene Therapy and the Boy Who Saved It, to be published by St. Martin’s Press.

*American Society of Gene and Cell Therapy, Washington, D.C., May 19-22, 2010

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