Gene Therapy for x-linked retinitis pigmentosa advancing
February 7, 2012 - Investigators from the University of Pennsylvania and the University of Florida have reported new advances towards a gene therapy for X-linked retinitis pigmentosa (XLRP). The team has successfully treated a group of dogs with a naturally occurring form of the disease.
X-linked RP is one of the more common genetic types of RP in humans, accounting for 10-20% of RP cases. It is due to mutations in the RPGR gene. The condition is much rarer in dogs, but this result is important because there are significant similarities in size and function between human and canine eyes. The same scientists were able to develop the first gene therapy for a retinal disease, a treatment that restored some vision to children with Leber congenital amaurosis due to defects in the RPE65 gene, in large part because they first developed the therapy and demonstrated its safety and effectiveness in affected dogs.
"Every single abnormal feature that defines [XLRP] in the dogs was corrected following treatment," says study scientist Dr. William Beltran, assistant professor of ophthalmology at Penn's School of Veterinary Medicine.
In this study, a single subretinal injection to the visually impaired dogs led to functional and structural recovery. The dogs' recovery was assessed using a variety of methods that are used clinically in patients, such as electroretinography and optical coherence tomography. This is the first proof that this condition is treatable in an animal model.
This study is also significant because it dealt with another major challenge in treating retinal eye disease. The first gene therapies were developed for conditions in which genetic defects prevent the retinal pigmented epithelium (RPE) from doing its job. The RPE is a layer of cells that support and nourish the photoreceptors (visual cells), but successful treatment of a problem in the RPE did not guarantee that a similar strategy would be effective for a problem that affects the photoreceptors directly. X-linked RP causes a protein defect within the photoreceptors themselves, and the new gene had to be targeted to both rod and cone photoreceptors in order to be fully effective.
To target these cells, the scientists used two strategies. To carry the new gene into the cell, they used a non-disease-causing virus known to target mainly rods and cones but not other cells. They also added a special piece of genetic material called a “promoter,” that would "switch on" the gene only if the virus penetrated the correct cell. Identifying the correct promoter was the job of the scientists from the University of Florida, Dr. William Hauswirth and Dr. Alfred Lewin – a task that required extensive cell studies.
"The study required a combination of genetic tools and surgical technique to make sure the therapy targeted only the diseased cells," says Dr. Gustavo Aguirre, who led the project at Penn.
The investigators were thrilled when the vision of the treated dogs improved, showing that they had succeeded in targeting the rod and cone photoreceptors. "We are intervening to treat both classes of photoreceptor cells, rods and cones, and that has never been done before in a large animal model," Beltran said. "And not only can we prevent the disease onset but also restore the remaining photoreceptors cells to normal once the disease is ongoing."
While the ability to repair both rods and cones was itself a first, the research team went further, showing that its treatment also repaired the photoreceptor connections to other retinal neurons that eventually send visual signals to the brain, another first.
"This not only provides hope for reversing XLRP but potentially for any form of photoreceptor degeneration," says Dr. Aguirre. "Altered inner retinal wiring is a common feature for these diseases that has been considered irreversible.
Many additional steps need to be taken before gene therapy for XLRP can be tested in humans. The researchers plan to repeat their studies in animals on a larger scale and over a longer term, and they will have to produce the viral vector used in the study according to human pharmaceutical standards and have it approved by regulatory authorities.
"While there is still much work to do to assess long-term efficiency and safety with this approach, there is hope that this vector and knowledge could be used in a few years to treat the many patients losing vision from XLRP," says Dr. Samuel Jacobson of the Scheie Eye Institute at the University of Pennsylvania.
This research was published January 18, 2011 in the early edition of the Proceedings of the National Academy of Sciences in the USA (PNAS).