Overview
Photoreceptors are light-detecting cells found in part of the eye known as the retina. Some inherited genetic faults can lead to photoreceptors that don’t work as they should, for example in X-linked retinitis pigmentosa and in Leber congenital amaurosis. Over time the cells can die off and in turn this leads to sight loss or blindness. We don’t understand exactly how and why this happens and there are no good treatments at the moment.
Researchers have found that it’s possible to turn skin cells into a type of stem cell that can then become many different types of cells in the body. These cells can be grown to form what’s known as an ‘optic cup’ – an early stage in eye development. But cells in the optic cup can’t sense light.
The team thinks that optic cup cells could become fully-working photoreceptors if they are transplanted into the right environment in the eye. In this project, they are:
- Transplanting optic cup cells into rodent eyes
- Studying the transplanted cells to see whether they start to behave like photoreceptors
- Comparing transplanted cells from rodents with sight loss to transplanted cells from rodents with healthy eyes.
- Testing two new therapies that might correct the genetic fault and lead to working photoreceptors
The results will tell us whether the potential new therapies are worth developing and may also lead to a new way of testing other new therapies for inherited retinal disorders and other conditions that cause sight loss.
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Scientific summary
Transplantation of human iPSC-derived photoreceptor progenitors into rodent retina to understand inherited retinal disease mechanisms and develop therapies.
There are no effective therapies for inherited retinal degeneration. Patient derived induced pluripotent stem cells (iPSC) offer the opportunity to effectively model disease in the lab and test potential therapies. For photoreceptor degeneration, this has been hampered by technical challenges in producing fully differentiated photoreceptors, but recent advances suggest this is now possible.
This project tests the hypothesis that iPSC can be used to study photoreceptor disease mechanisms and test potential therapies though developing a platform to study human iPSC-derived photoreceptors. The team is using iPSC from patients with X-linked retinitis pigmentosa and Leber congenital amaurosis caused by mutations in RP2 and CEP290 respectively. The iPSC are being differentiated into photoreceptor progenitors and their morphology studied in detail in comparison to those derived from control iPSC. The team then transplants the photoreceptor progenitors into mouse retina, so that they can complete their differentiation into ‘mature’ photoreceptors and investigate their disease associated phenotype. These ‘mature’ photoreceptors are then used to test gene and sequence dependent therapies; readthrough for an RP2 stop mutation and antisense oligonucleotide mediated suppression of aberrant splicing for an intronic mutation in CEP290. The preliminary data show that these approaches can restore functional protein and the team is testing if this is sufficient to rescue photoreceptor morphology and survival.
There is currently no other way to test these potential therapies for specific patient mutations and demonstration that iPSC can be used in this way will open up the possibility of using iPSC to study other diseases and novel treatments.