RARE DISEASE
X-linked retinoschisis
X-linked retinoschisis
X-linked retinoschisis
Synonyms: X-linked juvenile retinoschisis, XLRS
Synonyms: X-linked juvenile retinoschisis, XLRS
Synonyms: X-linked juvenile retinoschisis, XLRS
Drug discovery
8
drugs
With orphan designations
Overview
X-linked retinoschisis (XLRS) is an inherited retinal disorder affecting males, caused by mutations in the RS1 gene (Xp22.1) leading to impaired retinoschisin production and retinal layer splitting [1][6][9]. Characterized by macular schisis, reduced visual acuity (typically 20/60–20/120), and peripheral retinal involvement in 40-50% of cases [4][6][12]. Complications include retinal detachment (5-22%) and vitreous hemorrhage [10][19]. Management focuses on carbonic anhydrase inhibitors (e.g., dorzolamide) to reduce schisis cavities, amblyopia treatment, and surgical intervention for complications [8][12][16].
Therapies
Topical/systemic carbonic anhydrase inhibitors (e.g., dorzolamide) improve retinal structure and stabilize vision [12][16]
Vitreoretinal surgery for retinal detachment/vitreous hemorrhage (5-40% require intervention) [10][19]
Investigational gene therapies using subretinal AAV vectors (e.g., Atsena Therapeutics’ AAV.SPR) [3][16][20]
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare ophthalmic disorders
Research Papers
234 drug discovery papers about X-linked retinoschisis, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
234 drug discovery papers about X-linked retinoschisis, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | Randomised Clinical Trial to Evaluate the Efficacy of Acetazolamide for the Treatment of Cystoid Fluid Collections in X-Linked Retinoschisis: The AXIS Trial.
This trial aimed to evaluate the efficacy of oral acetazolamide in reducing cystoid fluid collections (CFC) and improving visual function in patients with X-linked retinoschisis (XLRS). In this investigator-initiated, single centre, open-label, randomised controlled trial, XLRS patients aged ≥ 12 years with fovea-involving CFC at baseline were eligible. Participants were randomised 1:1 to receive either oral acetazolamide (500 mg/day for 16 weeks, followed by tapering or discontinuation based on response) or no treatment (control) for 32 weeks. Seven study visits were completed over 32 weeks. The primary outcome was central subfield thickness (CST). Secondary outcomes included functional and structural measures, as well as patient-reported visual disability. A total of 19 patients were enrolled: 10 received acetazolamide (17 eyes), and nine were monitored without treatment (16 eyes). The difference in CST from baseline up to week 32 between the treatment and control groups was on average +2.7 μm (p = 0.9; 95% CI, -68.1 to 73.5 μm). Retinal sensitivity on microperimetry showed a modest statistically significant improvement favouring acetazolamide. However, no significant improvements were observed for best-corrected visual acuity, low-luminance visual acuity, cystoid fluid collection volume or patient-reported visual disability in the treatment group compared to the control group. This study found no clinically meaningful benefit of oral acetazolamide for reducing CFC or improving visual function in the overall XLRS population. Although structural and functional outcomes were comparable between groups overall, a small subset of patients may experience benefit, suggesting a personalised treatment approach may be warranted.
2026-06-05 | Modulation of Systemic Osmolarity Alters Retinal Thickness and Schisis Cavities Without Blood Retinal Barrier Disruption in Rs1 Knockout Mice.
The purpose of this study was to determine whether systemic osmolarity modulation through dehydration or hydration alters retinal thickness and schisis cavity area in Rs1 knockout (KO) mice compared with wild-type (WT) controls, and whether such changes occur without disruption of the blood-retinal barrier (BRB). Postnatal day 30 Rs1 KO and WT mice underwent dehydration (dry anesthesia) or hydration (intraperitoneal injection of distilled water, 40 mL/kg) during in vivo optical coherence tomography (OCT) imaging. Retinal thickness and schisis cavity area were quantified from serial OCT B-scans. BRB integrity was evaluated using fluorescein angiography (FA) and immunostaining of retinal and retinal pigment epithelium (RPE) junctional markers. Dehydration significantly reduced retinal thickness and schisis cavity area in Rs1 KO mice, with changes of greater magnitude than those observed in WT controls. Hydration increased retinal thickness in WT mice, whereas Rs1 KO mice had a relatively blunted and variable structural response compared to WT in both retinal thickness and schisis cavity area. FA and immunostaining revealed no evidence of vascular leakage or RPE junctional disruption in either genotype, indicating preserved BRB integrity under all experimental conditions. These results demonstrate that systemic osmolarity modulation alters retinal structure in X-linked retinoschisis (XLRS) through mechanisms independent of BRB disruption. The exaggerated response to dehydration and attenuated response to hydration in Rs1 KO suggest altered intraretinal fluid dynamics and biomechanical constraints associated with schisis cavities. These findings indicate that modulation of osmolarity may represent a potential therapeutic approach for intraretinal fluid accumulation in XLRS.
2026-04-01 | Intrafamilial variability in X-linked retinoschisis: Report of two affected brothers from a large family
X-linked retinoschisis (XLRS) is an inherited retinal dystrophy caused by mutations in the RS1 gene, typically presenting in young males with bilateral foveal schisis and variable peripheral involvement. We report the case of a 25-year-old male, the eighth of ten siblings, who presented with progressive diminution of vision in both eyes over the past 6 months. His best-corrected visual acuity was 6/18 in the right eye and 6/60 in the left eye. Fundus examination showed classical foveal schisis and spectral-domain optical coherence tomography (OCT) confirmed multilayer schitic cavities, more extensive in the left eye. A younger brother also demonstrated OCT-documented bilateral retinoschisis but with better visual acuity, highlighting intrafamilial phenotypic variability. Genetic testing could not be performed due to financial constraints, underscoring the diagnostic challenges in the resource-limited settings where multimodal imaging is indispensable. The proband was started on topical dorzolamide and oral acetazolamide, but no functional or structural improvement has been observed so far. This case contributes to the expanding clinical spectrum of XLRS, emphasizes variability in phenotypic expression within the same family, and illustrates the limitations of current treatment options while pointing toward the potential of emerging gene-based therapies.
2026-02-02 | Profound Effect of Light on Cysts in X-Linked Retinoschisis.
X-linked retinoschisis (XLRS), caused by RS1 pathogenic variants, leads to macular dystrophy. Patients with XLRS show diurnal changes in optical coherence tomography (OCT), with more schisis in the morning. We studied diurnal variation in Rs1-knockout (KO) mice retinal structure and electrical function. Rs1-KO mice 2.5 to 4 months old (MO) had electroretinogram (ERG), OCT, and intraocular pressure (IOP) measurements collected at 5 AM and 5 PM on different days and under different experimental conditions. Mice were maintained under standard 12-hour light/dark cycle, reversed 12-hour light/dark cycle, continuous light, or continuous darkness. At study endpoint, eyes were collected and fixed for immunohistochemistry or harvested for Western blot analysis. Extended light exposure resolved cysts completely and improved ERG b-wave amplitudes, whereas darkness worsened schisis and ERG function. Synaptic staining confirmed disrupted photoreceptor-bipolar connections in dark-exposed retinas and reorganization after light exposure, without changes in synaptic protein expression or rhodopsin localization. IOP still followed a diurnal pattern under constant light or dark, whereas cyst fluctuation correlated with lighting rather than time of day. Initial findings suggested a diurnal rhythm in cyst size but reversed light cycle experiments showed that light exposure-not time of day-drives retinal changes in Rs1-KO mice. RS1-deficient retinas are vulnerable to darkness, whereas light exposure preserves retinal structure and function. To ensure valid OCT and ERG comparisons in XLRS, measurements should be time- and lighting-stamped. Dark-adapted conditions may best reveal treatment effects. Controlled light exposure may be a therapeutic option for patients with XLRS.
2026-01-28 | Microglial phagocytosis of bipolar cells triggers inner retinal degeneration in Rs1-KO mice.
BACKGROUND: X-linked juvenile retinoschisis (XLRS) is a hereditary retinal disorder caused by mutations in the RS1 gene that leads to the formation of cavities in the inner nuclear layer (INL) and progressive vision loss, characterized by a disproportionate reduction of the b-wave compared to the a-wave in electroretinography (ERG). While previous research has largely focused on photoreceptor degeneration in XLRS, the specific roles of other cell populations, particularly bipolar cells and microglia, in the early stages of the disease have remained less well understood. Thus, this study aimed to elucidate the early cellular and molecular mechanisms of retinal degeneration in XLRS, with a particular focus on the role of microglia and bipolar cells. METHODS: Retinal structure and function were assessed in CRISPR/Cas9 Rs1-exon2 knockout (Rs1−/y) mice at 8 and 24 weeks using histology, spectral-domain optical coherence tomography (SD-OCT), ERG, and optokinetic response. To analyze cell-specific changes, we performed TUNEL assay, immunofluorescence, flow cytometry, and single-cell RNA sequencing (scRNA-seq) with trajectory analysis. RESULTS: Rs1−/y mice successfully recapitulated classic XLRS features, including INL schisis, reduced b/a-wave ERG ratio, and early vision loss. TUNEL assay and histological analysis revealed that cell death initiated in the INL at 8 weeks and progressed to the outer nuclear layer (ONL), while microglia displayed a progressive transition from a ramified to an ameboid morphology. scRNA-seq demonstrated a significant loss of cone bipolar cells, especially OFF-cone subtypes, which preceded photoreceptor degeneration. Importantly, microglial activation and enhanced phagocytosis of OFF-cone bipolar cells were observed prior to photoreceptor loss. This phagocytic process was found to be mediated by phosphatidylserine and complement C3b, independent of caspase-3 pathways. CONCLUSIONS: Our findings demonstrate that bipolar cell degeneration, driven by microglial phagocytosis of stressed yet viable OFF-cone bipolar cells, is an early and critical pathological event in XLRS that precedes photoreceptor loss. This process involves "eat-me" signals and complement activation independent of classical apoptosis. These results provide a new perspective on XLRS pathogenesis and suggest that therapeutic strategies targeting bipolar cells and microglial activity could offer promising avenues for early intervention.
2026-08-11 | Randomised Clinical Trial to Evaluate the Efficacy of Acetazolamide for the Treatment of Cystoid Fluid Collections in X-Linked Retinoschisis: The AXIS Trial.
This trial aimed to evaluate the efficacy of oral acetazolamide in reducing cystoid fluid collections (CFC) and improving visual function in patients with X-linked retinoschisis (XLRS). In this investigator-initiated, single centre, open-label, randomised controlled trial, XLRS patients aged ≥ 12 years with fovea-involving CFC at baseline were eligible. Participants were randomised 1:1 to receive either oral acetazolamide (500 mg/day for 16 weeks, followed by tapering or discontinuation based on response) or no treatment (control) for 32 weeks. Seven study visits were completed over 32 weeks. The primary outcome was central subfield thickness (CST). Secondary outcomes included functional and structural measures, as well as patient-reported visual disability. A total of 19 patients were enrolled: 10 received acetazolamide (17 eyes), and nine were monitored without treatment (16 eyes). The difference in CST from baseline up to week 32 between the treatment and control groups was on average +2.7 μm (p = 0.9; 95% CI, -68.1 to 73.5 μm). Retinal sensitivity on microperimetry showed a modest statistically significant improvement favouring acetazolamide. However, no significant improvements were observed for best-corrected visual acuity, low-luminance visual acuity, cystoid fluid collection volume or patient-reported visual disability in the treatment group compared to the control group. This study found no clinically meaningful benefit of oral acetazolamide for reducing CFC or improving visual function in the overall XLRS population. Although structural and functional outcomes were comparable between groups overall, a small subset of patients may experience benefit, suggesting a personalised treatment approach may be warranted.
2026-06-05 | Modulation of Systemic Osmolarity Alters Retinal Thickness and Schisis Cavities Without Blood Retinal Barrier Disruption in Rs1 Knockout Mice.
The purpose of this study was to determine whether systemic osmolarity modulation through dehydration or hydration alters retinal thickness and schisis cavity area in Rs1 knockout (KO) mice compared with wild-type (WT) controls, and whether such changes occur without disruption of the blood-retinal barrier (BRB). Postnatal day 30 Rs1 KO and WT mice underwent dehydration (dry anesthesia) or hydration (intraperitoneal injection of distilled water, 40 mL/kg) during in vivo optical coherence tomography (OCT) imaging. Retinal thickness and schisis cavity area were quantified from serial OCT B-scans. BRB integrity was evaluated using fluorescein angiography (FA) and immunostaining of retinal and retinal pigment epithelium (RPE) junctional markers. Dehydration significantly reduced retinal thickness and schisis cavity area in Rs1 KO mice, with changes of greater magnitude than those observed in WT controls. Hydration increased retinal thickness in WT mice, whereas Rs1 KO mice had a relatively blunted and variable structural response compared to WT in both retinal thickness and schisis cavity area. FA and immunostaining revealed no evidence of vascular leakage or RPE junctional disruption in either genotype, indicating preserved BRB integrity under all experimental conditions. These results demonstrate that systemic osmolarity modulation alters retinal structure in X-linked retinoschisis (XLRS) through mechanisms independent of BRB disruption. The exaggerated response to dehydration and attenuated response to hydration in Rs1 KO suggest altered intraretinal fluid dynamics and biomechanical constraints associated with schisis cavities. These findings indicate that modulation of osmolarity may represent a potential therapeutic approach for intraretinal fluid accumulation in XLRS.
2026-04-01 | Intrafamilial variability in X-linked retinoschisis: Report of two affected brothers from a large family
X-linked retinoschisis (XLRS) is an inherited retinal dystrophy caused by mutations in the RS1 gene, typically presenting in young males with bilateral foveal schisis and variable peripheral involvement. We report the case of a 25-year-old male, the eighth of ten siblings, who presented with progressive diminution of vision in both eyes over the past 6 months. His best-corrected visual acuity was 6/18 in the right eye and 6/60 in the left eye. Fundus examination showed classical foveal schisis and spectral-domain optical coherence tomography (OCT) confirmed multilayer schitic cavities, more extensive in the left eye. A younger brother also demonstrated OCT-documented bilateral retinoschisis but with better visual acuity, highlighting intrafamilial phenotypic variability. Genetic testing could not be performed due to financial constraints, underscoring the diagnostic challenges in the resource-limited settings where multimodal imaging is indispensable. The proband was started on topical dorzolamide and oral acetazolamide, but no functional or structural improvement has been observed so far. This case contributes to the expanding clinical spectrum of XLRS, emphasizes variability in phenotypic expression within the same family, and illustrates the limitations of current treatment options while pointing toward the potential of emerging gene-based therapies.
2026-02-02 | Profound Effect of Light on Cysts in X-Linked Retinoschisis.
X-linked retinoschisis (XLRS), caused by RS1 pathogenic variants, leads to macular dystrophy. Patients with XLRS show diurnal changes in optical coherence tomography (OCT), with more schisis in the morning. We studied diurnal variation in Rs1-knockout (KO) mice retinal structure and electrical function. Rs1-KO mice 2.5 to 4 months old (MO) had electroretinogram (ERG), OCT, and intraocular pressure (IOP) measurements collected at 5 AM and 5 PM on different days and under different experimental conditions. Mice were maintained under standard 12-hour light/dark cycle, reversed 12-hour light/dark cycle, continuous light, or continuous darkness. At study endpoint, eyes were collected and fixed for immunohistochemistry or harvested for Western blot analysis. Extended light exposure resolved cysts completely and improved ERG b-wave amplitudes, whereas darkness worsened schisis and ERG function. Synaptic staining confirmed disrupted photoreceptor-bipolar connections in dark-exposed retinas and reorganization after light exposure, without changes in synaptic protein expression or rhodopsin localization. IOP still followed a diurnal pattern under constant light or dark, whereas cyst fluctuation correlated with lighting rather than time of day. Initial findings suggested a diurnal rhythm in cyst size but reversed light cycle experiments showed that light exposure-not time of day-drives retinal changes in Rs1-KO mice. RS1-deficient retinas are vulnerable to darkness, whereas light exposure preserves retinal structure and function. To ensure valid OCT and ERG comparisons in XLRS, measurements should be time- and lighting-stamped. Dark-adapted conditions may best reveal treatment effects. Controlled light exposure may be a therapeutic option for patients with XLRS.
2026-01-28 | Microglial phagocytosis of bipolar cells triggers inner retinal degeneration in Rs1-KO mice.
BACKGROUND: X-linked juvenile retinoschisis (XLRS) is a hereditary retinal disorder caused by mutations in the RS1 gene that leads to the formation of cavities in the inner nuclear layer (INL) and progressive vision loss, characterized by a disproportionate reduction of the b-wave compared to the a-wave in electroretinography (ERG). While previous research has largely focused on photoreceptor degeneration in XLRS, the specific roles of other cell populations, particularly bipolar cells and microglia, in the early stages of the disease have remained less well understood. Thus, this study aimed to elucidate the early cellular and molecular mechanisms of retinal degeneration in XLRS, with a particular focus on the role of microglia and bipolar cells. METHODS: Retinal structure and function were assessed in CRISPR/Cas9 Rs1-exon2 knockout (Rs1−/y) mice at 8 and 24 weeks using histology, spectral-domain optical coherence tomography (SD-OCT), ERG, and optokinetic response. To analyze cell-specific changes, we performed TUNEL assay, immunofluorescence, flow cytometry, and single-cell RNA sequencing (scRNA-seq) with trajectory analysis. RESULTS: Rs1−/y mice successfully recapitulated classic XLRS features, including INL schisis, reduced b/a-wave ERG ratio, and early vision loss. TUNEL assay and histological analysis revealed that cell death initiated in the INL at 8 weeks and progressed to the outer nuclear layer (ONL), while microglia displayed a progressive transition from a ramified to an ameboid morphology. scRNA-seq demonstrated a significant loss of cone bipolar cells, especially OFF-cone subtypes, which preceded photoreceptor degeneration. Importantly, microglial activation and enhanced phagocytosis of OFF-cone bipolar cells were observed prior to photoreceptor loss. This phagocytic process was found to be mediated by phosphatidylserine and complement C3b, independent of caspase-3 pathways. CONCLUSIONS: Our findings demonstrate that bipolar cell degeneration, driven by microglial phagocytosis of stressed yet viable OFF-cone bipolar cells, is an early and critical pathological event in XLRS that precedes photoreceptor loss. This process involves "eat-me" signals and complement activation independent of classical apoptosis. These results provide a new perspective on XLRS pathogenesis and suggest that therapeutic strategies targeting bipolar cells and microglial activity could offer promising avenues for early intervention.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
8 orphan drug designations for X-linked retinoschisis.
8 orphan drug designations for X-linked retinoschisis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adeno-associated viral vector serotype 44.9 containing the human HRS1 gene | gene therapies | EMA | 2026-02-23 | — | Asphalion S.L. |
Recombinant adeno-associated virus 8 (AAV8) expressing human retinoschisin (RS1) gene | gene therapies | FDA | 2024-10-22 | — | Chengdu Genevector Biotechnology Co., Ltd. |
Engineered adeno-associated virus spreading capsid encapsulating a human retinoschisin (hRS1) transgene | gene therapies | FDA | 2024-08-21 | — | Atsena Therapeutics, Inc. |
Modified Recombinant adeno-associated virus (rAAV) serotype 2 vector, AAV.IVT18, expressing human retinoschisis gene RS1 driven by RS1 and CMV chimeric promoter | gene therapies | FDA | 2024-02-08 | — | InnoVec Biotherapeutics Inc. |
Recombinant adeno-associated virus (rAAV) vector expressing human retinoschisis protein RS1 | gene therapies | FDA | 2022-11-15 | — | Langxin Qisheng (Suzhou) Biopharmaceutical Co., Ltd. |
adeno-associated virus type 8 delivering a vector genome with human retinoschisin promoter (RS/IRBP) and the human retinoschisin cDNA (hRS) | gene therapies | FDA | 2015-11-16 | — | VegaVect, Inc. |
Recombinant adeno-associated viral vector containing the human retinoschisin gene | gene therapies | EMA | 2013-03-12 | — | Propharma Group The Netherlands B.V. |
adeno-associated viral vector expressing human retinoschisin-1 gene | gene therapies | FDA | 2007-05-21 | — | TeamedOn International, Inc. |
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