Biology subjects

Zrenner, E.

Publications and source records attributed to Zrenner, E..

3 recordsLinked to original sources

bioRxiv2026

A mutation-agnostic and allele-specific ASO strategy demonstrates potent functional rescue and retinal preservation in RHO-linked retinitis pigmentosa

Autosomal dominant retinitis pigmentosa (adRP) caused by RHO mutations is a leading form of inherited retinal degeneration. Extensive allelic heterogeneity of RHO pathogenic variants limits the translational applicability of mutation-specific gene therapies. To address this, we developed SNARE (SNP-guided Silencing of Aberrant RHO Expression), a mutation-independent, allele-specific antisense oligonucleotide (ASO) strategy. SNARE selectively suppresses mutant RHO transcripts by targeting the common, benign c.-26A/G single-nucleotide polymorphism (SNP) as an allelic discriminator. Candidate gapmer ASOs were screened in engineered reporter lines and validated in patient-derived retinal organoids, identifying RHOligo-A as the lead c.-26A-targeting candidate. In vitro, RHOligo-A achieved robust, preferential knockdown of the target allele, improving RHO localization in retinal organoids, and demonstrated a favorable safety profile with minimal transcriptomic off-target effects and no detectable immunostimulatory activity. Subsequent validation in a novel, humanized RHOP347L/WT mouse model, achieved sustained c.-26A-linked allele-selective suppression, retinal structure preservation, and significantly restored visual function, upon a single intravitreal administration. These findings establish RHOligo-A and SNARE as a scalable, mutation-independent therapeutic platform with strong translational potential and substantial clinical reach for RHO-associated adRP.

genetics↗

bioRxiv2025

Adaptation of visual responses in degenerating rd10 and healthy mouse retinas during ongoing electrical stimulation.

ObjectiveVisual adaptation is a physiological and perceptual process by which the visual system adjusts to changes in the environment or visual stimuli. This process is fundamental to how we perceive the world around us and allows our visual system to efficiently encode and process visual information. The retina incorporates adaptaion with its dozens of functionally distinct retinal ganglion cell types. Meanwhile, the field of retinal prostheses is increasing its understanding of electrical adaptation and cell-specific stimulation. However, very little is known about the interaction of visual and electrical stimulation on the adaptation of retinal ganglion cell types. Methods/ApproachRecording with a microelectrode array (MEA), we presented an ON and OFF full-field, visual stimulus to characterize various visual response parameters in healthy and degenerating rd10 mouse retinas. We then evaluated visual response changes before and after blocks of monophasic voltage-controlled electrical pulse stimulation. Main ResultsA history of electrical stimulation strengthened visual responses in WT retina, even when changes attributable to in vitro visual adaptation were taken into account. In rd10 retinas, electrical adaptation counteracted the baseline in vitro visual adaptation. In all cases, adaptation often affected the ON and OFF visual response components differentially. Consequently, the ON/OFF classification of indiviual cells changed as a result of adaptation. SignificanceElectrical stimulation-induced changes in the retina should be considered in the encoding of visual stimuli by retinal prosthetic devices. In vitro investigations for bionic vision should strive to probe electrical responsiveness after adaptation to ongoing electrical stimulation has achieved a steady-state.

neuroscience↗

bioRxiv2019

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors while cones remain initially unaffected. Cone death follows rod death secondarily due to increased oxidative stress, inflammation, and loss of structural and nutritional support provided by rods. Here, we show that secondary cone cell death in animal models for RP was associated with an increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at a late stage of the disease, when majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival. Moreover, the surviving cones remained light sensitive and initiated light-driven ganglion cell responses. RNA-seq analysis of protected cones demonstrated that HDAC inhibition led to multi-level protection via regulation of different pro-survival pathways, including MAPK, PI3K-Akt, and autophagy. This study suggests a unique possibility for a targeted pharmacological protection of both primary degenerating rods and secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients independent of the disease stage.

neuroscience↗