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A human-specific RPGR isoform and a clinically approved Rho/ROCK inhibitor ameliorate defects associated with RPGR
Muhammad Usman1, Paul Atigbire1, Dennis Kastrati1
1Human Genetics, Medical Faculty-School of Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, 26129 Oldenburg, Germany.
Molecular Therapy. Nucleic Acids
|December 1, 2025
Summary
Pathogenic variants in the retinitis pigmentosa GTPase regulator (RPGR) gene cause X-linked RP. The human-specific RPGR-s14/15 isoform is crucial for ciliary and actin integrity, and ripasudil treatment shows therapeutic potential.
Area of Science:
- Ophthalmology
- Genetics
- Cell Biology
Background:
- Pathogenic variants in the retinitis pigmentosa GTPase regulator (RPGR) gene are a leading cause of X-linked retinitis pigmentosa (RP), a condition causing photoreceptor degeneration.
- RPGR dysfunction is linked to defects in ciliary structure and actin dynamics, crucial for photoreceptor function.
- The function of the human-specific RPGR isoform (RPGRs14/15) is poorly understood, despite the urgent need for RPGR-associated RP treatments.
Purpose of the Study:
- To investigate the role of RPGR isoforms, particularly RPGRs14/15, in maintaining ciliary integrity and actin turnover.
- To identify potential therapeutic strategies for RPGR-associated RP.
Main Methods:
- Generated RPGR mutant hTERT-RPE1 cell lines lacking all RPGR isoforms (RPGR_KO).
- Assessed ciliary structure (length, segmentation) and actin dynamics in RPGR_KO cells and cells expressing only RPGRs14/15.
- Utilized pharmacological agents: cytochalasin D (CytoD) to disrupt actin polymerization and ripasudil (a Rho/ROCK inhibitor) to test for rescue effects.
Main Results:
- Loss of all RPGR isoforms in RPGR_KO cells caused significant ciliary defects and disrupted actin turnover.
- Cells expressing only the human-specific RPGRs14/15 isoform largely prevented these defects, highlighting its critical role.
- Pharmacological disruption of actin polymerization mimicked RPGR-deficiency phenotypes.
- Ripasudil treatment effectively rescued both ciliary and actin-related defects in RPGR_KO cells without apparent side effects.
Conclusions:
- The human-specific RPGRs14/15 isoform plays a vital role in maintaining ciliary integrity and actin dynamics.
- Ripasudil demonstrates significant therapeutic potential for treating RPGR-associated retinal degeneration by addressing both ciliary and actin-related defects.
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