Journal article
An osmolarity dependent mechanism partially ameliorates retinal cysts and rescues cone function in a mouse model of X-linked retinoschisis
Frontiers in medicine, Vol.11, 1302119
10/15/2024
DOI: 10.3389/fmed.2024.1302119
PMCID: PMC11518720
PMID: 39473494
Abstract
Introduction X-linked retinoschisis (XLRS) is a vitreoretinal dystrophy caused by RS1 gene mutations which disrupt retinoschisin-1 (RS1) function. Vital for retinal architecture, the absence of functional RS1 leads to the development of intraretinal cysts. Intravitreal injection of a gene therapy for treating XLRS caused ocular inflammation in high dose groups in a phase I/II clinical trial. This study investigates a low dose subretinal gene therapy in Rs1 knockout ( Rs1 -KO) mice compared to injection of buffer alone. Observation of an unexpected therapeutic effect following the subretinal injection of the hypertonic buffer led to novel findings in XLRS. Methods Rs1 -KO mice were subretinally injected with an AAV2/4 vector ( n = 10) containing the RS1 gene driven by an Ef1α promoter, a hypertonic buffer ( n = 15) (180 mM NaCl 0.001% F68/PBS (pH 7.4)), or isotonic buffer ( n = 7) (155.2 mM NaCl 0.001% F68/PBS, pH 7.0). A sham puncture group was also included ( n = 6). Endpoints included electroretinogram (ERG), optical coherence tomography (OCT), a visually guided swim assay (VGSA), and immunohistochemistry. Results Unexpectedly, hypertonic buffer-injected eyes had reduced cyst severity at 1-month post-injection (MPI) ( p < 0.0001), higher amplitudes in cone-dominant ERGs persisting to 5 MPI (5 Hz flicker; p < 0.0001; 3.0 flash; p = 0.0033) and a trend for improved navigational vision in the light compared to untreated Rs1 -KO eyes. To investigate the role of tonicity on this effect, an isotonic buffer-injected cohort was created (155.2 mM NaCl 0.001% F68/PBS, pH 7.0) ( n = 7). Surprisingly, hypertonic buffer-injected eyes exhibited a greater reduction in cyst severity and demonstrated improved cone-dominant ERG metrics over isotonic buffer-injected and sham puncture eyes. An immunohistochemistry assay demonstrated greater cone density in hypertonic buffer-injected eyes than untreated Rs1 -KO eyes at 5–6 MPI ( p = 0.0198), suggesting a possible cone preservation mechanism. Moreover, our findings reveal a negative correlation between the peak severity of cysts and long-term ERG amplitudes in cone-dominant pathways, implying that effectively managing cysts could yield enduring benefits for cone function. Discussion/conclusion This study presents evidence that cyst resolution can be triggered through an osmolarity-dependent pathway, and early cyst resolution has long-term effects on cone signaling and survival, offering potential insights for the development of novel treatments for XLRS patients.
Details
- Title: Subtitle
- An osmolarity dependent mechanism partially ameliorates retinal cysts and rescues cone function in a mouse model of X-linked retinoschisis
- Creators
- Ella J. Gehrke - University of IowaJacob Thompson - University of IowaEmily Kalmanek - University of IowaSarah T. Stanley - University of IowaJoseph Laird - University of IowaSajag Bhattarai - University of IowaBrianna Lobeck - University of Iowa, Ophthalmology and Visual SciencesSara Mayer - University of IowaAngela Mahoney - University of IowaSalma Hassan - University of IowaYing Hsu - University of IowaArlene Drack - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Frontiers in medicine, Vol.11, 1302119
- DOI
- 10.3389/fmed.2024.1302119
- PMID
- 39473494
- PMCID
- PMC11518720
- NLM abbreviation
- Front Med (Lausanne)
- ISSN
- 2296-858X
- eISSN
- 2296-858X
- Publisher
- FRONTIERS MEDIA SA
- Grant note
- Chakraborty Family Foundation
The authors would like to thank Dalyz Ochoa and Budd Tucker Ph.D. for providing the AAV2/4-EF1 alpha-RS1 vector for this study. The authors would also like to thank Paul Sieving M.D., Ph.D. for providing us with the Rs1-KO mouse line.
- Language
- English
- Date published
- 10/15/2024
- Academic Unit
- Stead Family Department of Pediatrics; Biochemistry and Molecular Biology; Ophthalmology and Visual Sciences
- Record Identifier
- 9984736738402771
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