Gene therapy may boost success of lung transplants

• A new gene therapy procedure to restore function in lungs damaged during harvesting from donors could make more of the organs available for transplanting, Canadian researchers reported Wednesday.

• Currently, only about 15% of potential donor lungs are used because the rest are too damaged to implant. The new technique, which has not yet been tested in humans, could prevent that damage or even reverse it, potentially expanding the supply of lungs sharply.

• Lung transplants are the definitive therapy for many end-stage lung diseases such as emphysema and cystic fibrosis, but they are fraught with problems. Because lungs are more likely to be rejected by recipients' bodies than other organs, the five-year survival rate is only about 50%, lower than that for heart, liver or kidney transplantation.

• And because of the shortage of donor lungs, an estimated 234 people in the United States died last year while waiting for a lung transplant, according to the Organ Procurement and Transplantation Network. About 1,800 people in this country are now on the waiting list for a lung, the agency said.

• The problem in both cases is inflammation caused by insufficient amounts of an immune molecule called lL-10. Donated lungs are immediately chilled on ice, which destroys any IL-10 that may remain in the lungs, allowing substantial damage to occur before the organ can be implanted. And a lack of the molecule after transplantation increases the likelihood that inflammation will damage the organ and induce rejection.

• To circumvent inflammation, Dr. Shaf Keshavjee and Dr. Marcelo Cypel of the University Health Network in Toronto and their colleagues developed a two-pronged approach.

1. First, they devised a domed chamber that keeps the lungs at body temperature, preserving IL-10, and that pumps a solution containing oxygen and nutrients through the lungs to keep them alive. That alone prevented the lungs from deteriorating and improved the success of transplants in animals.
2. The researchers then performed gene therapy on the lungs, using a defanged adenovirus to deliver a gene that is the blueprint for IL-10 into the lung tissue. The gene was quickly taken up by the cells and began producing the molecule, which reduced inflammation.

• The team reported Wednesday in the new journal Science Translational Medicine that they used the technique to remove lungs from pigs -- whose metabolism is similar to that of humans -- perfused them in the domed chamber for 12 hours, then successfully re-implanted them.

• They then took human lungs that were considered too damaged for transplantation and subjected them to the same procedure. The treatment significantly improved blood flow through the lungs and improved their ability to take in fresh oxygen and remove carbon dioxide. The higher levels of IL-10 persisted in the lungs for 30 days, suggesting that the procedure could also reduce rejection of the organs. The lungs were not implanted in humans.

http://www.latimes.com/news/nationworld/nation/la-sci-lungs29-2009oct29,0,6019138.story

Gene therapy transforms eyesight of 12

• Pennsylvania researchers using gene therapy have made significant improvements in vision in 12 patients with a rare inherited visual defect, a finding that suggests it may be possible to produce similar improvements in a much larger number of patients with retinitis pigmentosa and macular degeneration.
  

• The team last year reported success with three adult patients, an achievement that was hailed as a major accomplishment for gene therapy. They have now treated an additional nine patients, including five children, and find that the best results are achieved in the youngest patients, whose defective retinal cells have not had time to die off.

• Today, after a single injection of a gene-therapy product in one eye, he rides his bike around the neighborhood, needs no assistance in the classroom, navigates the obstacle course quickly and has even played his first game of softball.

• The study "holds great promise for the future" and "is appealing because of its simplicity," wrote researchers from the Nijmegen Medical Center in the Netherlands in an editorial accompanying the report, which was published online Saturday by the journal Lancet.

• The 12 patients had Leber's congenital amaurosis, which affects about 3,000 people in the United States and perhaps 130,000 worldwide. Victims are born with severely impaired vision that deteriorates until they are totally blind, usually in childhood or adolescence. There is no treatment.

• Leber's is a good candidate for gene therapy because most of the visual apparatus is intact, particularly at birth and in childhood. Mistakes in 13 different genes are known to cause it, but all 12 of the patients suffered a defect in a gene called RPE65. This gene produces a vitamin A derivative that is crucial for detecting light.

• About five children are born each year in the United States with that defect, which was chosen because researchers at the Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine had cloned the gene, making copies available for use.

• The study, led by Dr. Katherine A. High, Dr. Albert M. Maguire and Dr. Jean Bennett of those two institutions, enrolled five people in the United States, five from Italy and two from Belgium. Five were children, and the oldest was 44.

• The good copy of the RPE65 gene was inserted into a defanged version of a human adenovirus. The engineered virus then invaded retinal cells and inserted the gene into the cells' DNA.

• Maguire used a long, thin needle to insert the preparation into the retina of the worst eye in each of the patients. Within two weeks, the treated eyes began to become more sensitive to light, and within a few more weeks, vision began to improve. The younger the patients were, the better they responded. That was expected, Bennett said, because similar results had been observed in dogs and rodents.

• By both objective and subjective measures, vision improved for all the patients. They were able to navigate obstacle courses, read eye charts and perform most of the tasks of daily living. The improvement has now persisted for as long as two years.

• There are clear limitations to the study. The patients' vision was not corrected to normal because of the damage that had already been done to the retina, and only one eye was treated.

• "The big elephant in the room is: Can you treat the other eye?" Rose said.

• Leber's is one form of retinitis pigmentosa, which affects an estimated 100,000 Americans. The findings might be applicable to macular degeneration, which affects an estimated 1.25 million Americans and is the major cause of visual impairment in the elderly.

http://www.latimes.com/news/nationworld/nation/la-sci-gene-therapy25-2009oct25,0,2334183.story