gms | German Medical Science

Motivation: Retinal remodeling and reprogramming are events triggered in all types of retinal degenerations in all species and are progressive, continuing to alter the fundamental architecture and function of the remnant retina throughout life. The mechanisms regulating these events are unknown, but most non-neural elements such as Müller cells, retinal pigmented epithelium cells, microglia, vascular endothelial cells and possibly astrocytes interact to create a novel milieu for large-scale remodeling and reprogramming.

Results: Remodeling involves extensive revisions in connectivity and includes the abundant generation of new ectopic axon-like processes by survivor neurons. We are exploring the endogenous generations of retinoic acid as a regulator of de novo axonogenesis via retinoic acid receptor (RAR) signaling. A more challenging process is reprogramming in cone-sparing retinitis pigmentosa, where ON bipolar cells begin to express AMPA/KA ionotropic receptors, changing their polarity and gain. First discovered in human RP retina, we have now demonstrated it in the rhodopsin P347L transgenic rabbit, a model of human autosomal dominant RP. While only 30% of bipolar cells have OFF polarity in the normal retina, 70–90% (including all rod bipolar cells) have OFF response attributes in advanced adRP.

Conclusions: The implications of these findings are several. First, all of these alterations complicate every late intervention (genetic, cellular, bionic) in late stage (NLP) RP arising form photoreceptor gene defects. Second, genetic profiling of candidate patients may be necessary to properly stratify outcome statistics. Third, as we are learning the triggers of remodeling and reprogramming, we are also encountering possible interventions to improve the outcomes of genetic, cellular, bionic treatments for blinding diseases.

This lecture is available as video recording (Attachment 1 [Attach. 1]).