How does scarring in the retina affect the chances of successful cell replacement therapy?
- Type of funding: Project Grant
- Grant Holder: Dr Rachel Pearson
- Institute: UCL Institute of Ophthalmology
- Region: London
- Start date: October 2015
- End Date: December 2017
- Priority: Treatment
- Eye Category:
Cell replacement therapy could become an important way to treat blindness due to loss of the light-detecting ‘photoreceptor’ cells in the eye. For it to work, donor cells need to be transplanted into the eye, move into the right position and connect up with other cells.
Previous research by the team gave the first concrete proof that it can work. They were able to give some sight back to mice with a type of night blindness. They also found that whether a transplant succeeds depends on which particular condition the mice had. The question is, why?
When photoreceptors die, support cells nearby start forming a scar. We don’t know exactly why but it could be an attempt to protect the rest of the eye by building a barrier around the lesion. But the barrier might also make it harder for transplanted donor cells to move into position and get connected.
So in this project the researchers will study four groups of mice to find out what happens to support cells in the process of forming a scar after photoreceptor loss. One group will have a disorder that follows the same course as Leber congenital amaurosis, and the other groups will each have one of three variations of retinitis pigmentosa.
The researchers aim to understand which steps in the process of forming a scar in the retina are important for whether or not cell transplants succeed. They will also try to find ways to improve the chances of donor cells getting into position and wiring up.
Defining strategies to modulate gliosis to achieve robust integration of transplanted photoreceptors into the diseased retina
Despite very different aetiologies, age-related macular degeneration (AMD) and most inherited retinal disorders culminate in the same final common pathway, loss of the photoreceptors. There are few clinical treatments and none can reverse the loss of vision. Photoreceptor replacement by transplantation is proposed as a broad treatment strategy applicable to all degenerations. The team has previously demonstrated restoration of vision by rod-photoreceptor transplantation. Most recently, they performed the first comprehensive assessment of rod-photoreceptor transplantation across different models of inherited photoreceptor degeneration. They found that photoreceptor transplantation is feasible in all models examined, but disease type impacts significantly on both the number and morphology of integrated rods.
A major determinant of transplant success is the extent of recipient retinal gliosis, which represents both a reservoir of inhibitory extracellular matrix (ECM) molecules and a physical barrier to cell migration. Understanding gliosis, how this process differs in different types of degeneration and finding strategies to circumvent the barriers formed represent major challenges to the advancement of cell- and gene-based therapies in the eye. To address these, the team will i) determine the changes in ECM composition occurring during degeneration, ii) define strategies to break down inhibitory ECM components of the glial scar, iii) manipulate integrin expression in transplanted photoreceptors to make them ‘blind’ to inhibitory cues, iv) determine the role of intermediate filament proteins in Muller glial hypertrophy and whether hypertrophy impairs photoreceptor integration, and v) assess the impact of manipulating the ECM and glial hypertrophy on transplanted photoreceptor migration and integration.
Results from the study published in the journal PLoS ONE reveal a wide variation in the way scars form in the retina between different inherited eye conditions. The differences aren’t related to the stage of the condition.
Hippert C, Graca AB, Barber AC, West EL, Smith AJ, Ali RR, et al. Müller Glia Activation in Response to Inherited Retinal Degeneration Is Highly Varied and Disease-Specific. PLoS ONE [Internet]. 2015 Mar 20;10(3):e0120415.