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Repairing DNA, One Cell at a Time

Published on January 16, 2014 in Cornerstone Blog · Last updated 3 years 8 months ago


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After decades of being “the next big thing,” gene therapy is here. And it’s working.

Of all the accomplishment a scientist can make, Katherine High, MD, can claim one of almost Biblical proportions: She made blind people see.

High would protest that it’s a bit more complicated — she worked together with Jean Bennett, MD, PhD, and Albert Maguire, MD, at the University of Pennsylvania, and their team restored only some of the patients’ sight — but the fact remains: This work allowed people who were legally blind to now recognize faces, see objects and better navigate the world.

High is one of the world’s leading experts in gene therapy, which has long been a “next big thing” in medicine: Take a person with a devastating genetic disease and replace their nonfunctional gene with a normal one — a cure built right into your DNA. It sounds elegantly simple, but it is among the most complex endeavors in all of medicine.

Finally, after decades of work, the future has arrived. High and her team at CHOP’s Center for Cellular and Molecular Therapeutics have produced clinical trials that show real results in humans, first with a type of inherited blindness called Leber’s congenital amaurosis (LCA), and more recently with the blood clotting disorder hemophilia B. Both are relatively rare conditions, but they are clear proof of concept — gene therapy works.

At its most basic level, gene therapy is all in the delivery. To move microscopic snippets of DNA into the body, High’s team uses adeno-associated virus (AAV) vectors, essentially envelopes of molecules engineered to look like a common virus. But instead of delivering a nasty payload of viral DNA, it delivers a normal gene that the recipient needs. They are so essential to gene therapy research that when a biotechnology company stopped making them in 2004 — not enough short-term profits — CHOP created its own clinical-grade production facility. (It also produces lentivirus vectors used to treat cancer patients like Emma Whitehead. See Page 16.)

Precisely engineering these particles is just one challenge; preventing the immune system from destroying them is another. “In a sense, viruses and the human immune response have been conducting a war for millions of years,” explains High. “The human immune system evolves to fight the virus, and then the virus makes some change to get around the immune system. It’s like the arms race.”

It turns out gene therapy also has something in common with real estate: location, location, location. It has worked well in the eye, where the immune system is relatively less aggressive, but has been more difficult elsewhere. “It has become a set of problems where each tissue — liver, skeletal muscle, blood — has a different set of answers,” High explains.

High’s breakthrough clinical trial came in 2007. Twelve patients with LCA-related blindness, including four children, received a gene therapy injection in one eye and demonstrated dramatic improvement in vision. A follow-up study last year treated the second eye in the same patients, with similar success. The team now has approval for a new trial to treat both eyes simultaneously. If successful, the treatment could be submitted for Food and Drug Administration approval as soon as 2015, and treatments for numerous other retinal diseases could follow.

High has also been working since the mid-1980s on gene therapy for hemophilia. The liver, where the blood’s clotting factors are made, is a trickier proposition. She led a clinical trial in 2001 that partially cured a man with hemophilia B, however the effects lasted only four weeks. His body’s immune system rallied to defeat the replacement gene. High, described by her colleagues as “energetic” and “dynamic,” returned to her lab and kept working.

In 2011, she was a collaborator in a study that took place in London that finally achieved the desired result: Six patients with hemophilia B are now producing enough clotting factor on their own to reduce or eliminate the need for clotting factor infusions. High hopes to extend this success with a new trial of 10 to 15 hemophilia patients that began at CHOP in January.

A mother of three, an avid late-night reader and a World War II buff, High grew up in North Carolina. She considered becoming a chemist like her grandfather — he taught at Penn, and a photo of him boating on the Schuylkill River sits atop her office shelves — but instead pursued medicine. As a hematology resident, she became interested in hemophilia A and B, the genes for which had just been identified.

“When I started in the 1980s, I thought it was going to be a big deal if we could just cure the disease in animals,” High says with a smile. “Now it’s much more fun because while there are still many problems that need to be solved, we know gene therapy works in certain subgroups of people.

We are working to develop solutions that will allow us to extend these therapies to ever larger numbers of patients. It’s really exciting.” From the latest issue of Children’s View.