Project Details
Projekt
Programming retinal Müller glial cells for supporting neuronal survival in retinal degeneration
Subject Area
Ophthalmology
Cell Biology
Cell Biology
Term
from 2018 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 399415314
Inherited retinal dystrophies (IRD) are rare disorders of the retina that cause degeneration of photoreceptors and thus result in severe decline of visual ability for the affected patients. The causative mutations driving IRD are extremely complex covering so far more than 200 known genes. Since only a smaller fraction of those mutations affect cone photoreceptors, while on the other hand, cones are the main photoreceptor cell type used in daylight vision, an important therapeutic concept is to preserve cone function independent of developing corrective gene therapies for any underlying mutation. Many neuroprotective factors effective against photoreceptor degeneration have been identified and most of them are normally provided by retinal Müller glial cells (RMG), the main glial cell of the retina, for preserving photoreceptor function throughout life. However, under IRD conditions, the intrinsic support provided by RMG is insufficient and we hypothesize that boosting the neuroprotective properties of RMG will prolong photoreceptors survival and retinal function in IRD.We aim to achieve this by CRISPR/(d)CAS9-driven re-programming of RMG into a neuroprotective phenotype and simultaneously suppressing adverse glial responses by interfering with gliotic/immune responses. We will focus on four different neurotrophic factors, namely, CNTF and GDNF, which both represent the as yet most effective neuroprotective factors in IRD. Further we will include CXCL10, a novel RMG-derived neurotrophic factor that we previously validated for a direct pro-survival effect on photoreceptors and finally, we will explore RdCVF, a rod-derived neurotrophic factor that was found to directly support cone survival, but is not naturally expressed by RMG. The models we will be using are primary RMG isolated from pigs as well as organotypic retinal explants, which will enable to target RMG in the intact tissue context. The final goal of this project is development of a pro-survival phenotype of RMG within the intact tissue context by simultaneous activation of pro-survival protein expression and inhibition of gliotic/inflammatory reactions.This will provide a completely novel and mutation-independent therapeutic strategy that might overcome previous limitations of neuroprotective therapy and eventually prevent disease progression and thus preserve fragile photoreceptors before corrective gene therapy or gene addition therapy becomes available for the individual patient. It also could be envisioned to be applicable to patients, which have already lost all rod photoreceptors and hence are too far progressed for corrective gene therapy, but still have residual cone-driven vision, which could be preserved. Further, this therapy may also be applicable beyond IRD to other degenerative diseases of the retina, such as glaucoma, age-related macular degeneration and diabetic retinopathy.
DFG Programme
Priority Programmes
