Retinitis Pigmentosa or RP is the most common form of inherited blindness. There are many different genes involved in the onset of RP. Molecular defects in more than 40 different genes can cause “isolated RP” and defects in more than 50 different genes can cause “syndromic RP.” Not only are there a host of different genes involved in RP, two patients with exactly the same molecular lesion can have a type of RP that differs substantially in its presentation.
The retina at the back of the eye is composed of two thick layers known as the inner neural retina and the outer pigmented retina. The neural retina consists of an outer layer of photoreceptors that are connected to an inner layer of bipolar cells. The bipolar cells connect with ganglion cells that have axons that extend to the optic nerve. The photoreceptor cells have their tips embedded in the pigmented retina, and the pigmented retina maintain and nourish the photoreceptors.
If the pigmented retina does not function properly, then the effects are most profoundly displayed in the photoreceptors. Photoreceptors respond to light and the constant exposure to light causes the photoreceptors to take a beating. The byproducts of all that light-induced damage accumulates at the tips of the photoreceptors cells, and these rubbish-filled tips are taken a gulped down by the cells of the pigmented retina. The pigmented retina cells degrade the damaged byproducts and recycle the precursor molecules. Without properly functioning pigmented retina cells, the photoceptors cells accumulate toxic light damage and then eventually die. Photoreceptor cell death is the end product of RP, and it results in blindness.
There is no cure for RP, and the treatments available are very hit-and-miss. For this reason, cell therapies have been examined in a variety of animal models of RP, which, in many cases, closely mimic the human disease to some degree.
Two different experimental treatments, one with induced pluripotent stem cells (iPSCs) and another with gene therapy have produced long-term improvement in visual function in mice with RP. These studies have been conducted at the Columbia University Medical Center (CUMC).
Stephen Tsang, associate professor of pathology, cell biology and ophthalmology who led both studies commented: “While these therapies still need to be refined, the results are highly encouraging. We’ve never seen this type of improvement in retinal function in mouse models of RP. We hope we may finally have something to offer patients with this form of vision loss.”
In one study, CUMC researchers tested the long-term safety and efficacy of iPSC grafts into the pigmented retina to restore visual function in a mouse model of RP. The mice were injected with undifferentiated iPSCs when they were five years old, and the cells differentiated into retinal pigmented epithelial (RPE) cells and integrated into the retinas. None of the mice that received these transplantations developed tumors over their lifetimes.
To test the effects of the implanted cells on the vision of the mice, Tsang’s group used electrophysiological measurements of the retina. In RP mice, as they become blind, the electrophysiology of the retina becomes rather abnormal, but in these mice implanted with the iPSCs, the electrophysiology of their retinas were not only normal, but stayed normal for a long period of time.
According to Tsang: “This is the first evidence of lifelong neuronal recovery in an animal model using stem cell transplants, with vision improvement persisting throughout the lifespan.”
In 2011, the FDA approved clinical trials of embryonic stem cell (ESC) transplants for the treatment of macular degeneration, but this treatment requires the application of drugs that suppress the immune system. Such drugs have rather nasty side effects.
“Our study focused on patient-specific iPS cells, which offer a compelling alternative,” Tsang said. “The iPS cells can provide a potentially unlimited supply of cells for functional rescue and optimization. Also, since they would come from a patient’s own body, immunosuppression would not be necessary to prevent rejection after transplantation.”
Theoretically, iPSC transplants, could also be used to treat age-related macular degeneration, which is the leading cause of vision loss in older adults.
In a second approach to treating RP, CUMC scientists tested a gene therapy protocol in RP mice. A specific type of RP that results from mutations in a PDE6alpha gene was used as a model system for gene therapy protocol. This particular type of RP is rather common in humans. The CUMC scientists injected a virus into one of the eyes of afflicted mice. This virus was engineered to express the PDE6alpha gene when it entered cells. Because this virus is the AAV or adenovirus-associated virus, it only spreads in the presence of adenovirus. Without a helper adenovirus in the retina, the engineered virus particles will infect the cells they initially contact, but they will not produce a productive infection. However, ferry the genes inside them to the cell they initially infect. This the engineered AAV particles are excellent vehicles for getting genes inside cells without causing an infection.
Examination of the mice six months later, the photoreceptors in the AAV-treated eyes were healthy and these eyes were able to see, but the uninjected eyes were unable to see and their photoreceptors were mostly dead.
Again Tsang commented: “These results provide support that RP due to PDE6alpha deficiency in humans is also likely to be treatable by gene therapy.”
CUMC and its teaching-hospital affiliate, New York-Presbyterian Hospital are part of an international consortium that was recently formed to bring this PDE6A gene therapy to patients. Pending FDA approval, clinical trials could begin within a year.
See Li, Y., Tsai, Y.T., Hsu, C.W., Erol, D., Yang, J., Wu, W.H., Davis, R.J., Egli, D., and Tsang, S.H. Long-term safety and efficacy of human induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa. Mol Med. 2012 Aug 9. doi: 10.2119/molmed. 2012.00242. [Epub ahead of print] (2012).
Wert KJ, Davis RJ, Sancho-Pelluz J, Nishina PM, Tsang S.H. Gene therapy provides long-term visual function in a pre-clinical model of retinitis pigmentosa. Hum. Mol. Genet. (2012) doi: 10.1093/hmg/dds46