Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors

Vijayasarathy, Camasamudram; Zeng, Yong; Marangoni, Dario; Dong, Lijin; Pan, Zhuo‐Hua; Simpson, Elizabeth M.; Fariss, Robert N; Sieving, Paul A.

doi:10.1167/iovs.63.11.8

Cited by 5 publications

(11 citation statements)

References 61 publications

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“…However, our study demonstrated that photoreceptor cells were developmentally delayed at RS1 mutation ROs. Besides the photoreceptor cells, we also identified Müller glial cells and bipolar cells, which are considered to be related to XLRS [54][55][56]. However, the number of Müller glial cells and bipolar cells did not differ significantly between patient and control ROs at day 260.…”

Section: Discussionmentioning

confidence: 77%

Retinal organoids with X-linked retinoschisis RS1 (E72K) mutation exhibit a photoreceptor developmental delay and are rescued by gene augmentation therapy

Duan,

Ding,

Sun

et al. 2024

Stem Cell Res Ther

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Background X-linked juvenile retinoschisis (XLRS) is an inherited disease caused by RS1 gene mutation, which leads to retinal splitting and visual impairment. The mechanism of RS1-associated retinal degeneration is not fully understood. Besides, animal models of XLRS have limitations in the study of XLRS. Here, we used human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs) to investigate the disease mechanisms and potential treatments for XLRS. Methods hiPSCs reprogrammed from peripheral blood mononuclear cells of two RS1 mutant (E72K) XLRS patients were differentiated into ROs. Subsequently, we explored whether RS1 mutation could affect RO development and explore the effectiveness of RS1 gene augmentation therapy. Results ROs derived from RS1 (E72K) mutation hiPSCs exhibited a developmental delay in the photoreceptor, retinoschisin (RS1) deficiency, and altered spontaneous activity compared with control ROs. Furthermore, the delays in development were associated with decreased expression of rod-specific precursor markers (NRL) and photoreceptor-specific markers (RCVRN). Adeno-associated virus (AAV)-mediated gene augmentation with RS1 at the photoreceptor immature stage rescued the rod photoreceptor developmental delay in ROs with the RS1 (E72K) mutation. Conclusions The RS1 (E72K) mutation results in the photoreceptor development delay in ROs and can be partially rescued by the RS1 gene augmentation therapy.

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Section: Discussionmentioning

confidence: 77%

Retinal organoids with X-linked retinoschisis RS1 (E72K) mutation exhibit a photoreceptor developmental delay and are rescued by gene augmentation therapy

Duan,

Ding,

Sun

et al. 2024

Stem Cell Res Ther

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“…It is predominantly expressed in the inner photoreceptors and bipolar cells [4]. There are reports supporting that RS1 expression is significantly lower in retinoschisis patients [5] and that RS1 gene therapy is effective in resolving retinoschisis in RS1-knockout mice [6,7]. RS1 plays an important role in maintaining an anatomically normal and functional macula.…”

Section: Discussionmentioning

confidence: 99%

Schisis-like Cystoid Macular Edema in Eyes with Diffuse Laser-treated Scars

Choi,

Lee

2023

J Retin

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Purpose:We sought to describe the clinical and imaging characteristics of eyes with schisis-like cystoid macular edema (CME) with diffuse areas of laser scar and determine their relationships. Methods: This was a retrospective cross-sectional review of eight eyes with schisis-like CME with diffuse area of laser scar. Laser treatment was performed during retinal surgery in the same eye. Data were collected from May 2019 (the baseline assessment date) to May 2023. Areas of diffuse laser scarring were evaluated on widefield photographs. Layers of schisis-like lesions were evaluated manually on optical coherence tomography images. Any trends or differences were compared among eyes. Results: All eyes had splitting between the inner nuclear and outer plexiform layers. Three eyes had additional splitting between the outer nuclear and outer plexiform layers. Four eyes achieved CME reductions by intravitreal triamcinolone treatment. Regions of retinal laser scar were infero-temporal in four cases, infero-nasal in one case, supero-temporal in one case, and both infero-nasal and infero-temporal in two cases. The location of schisis-like CME was infero-temporal in four cases, inferior in one case, supero-temporal in one case, infero-nasal in two cases, and of uniform distribution in one case. The locations of diffuse laser scars and the locations of schisis-like CME showed correspondence. Conclusions: A wide area of laser-applied scar on the retina may contribute to the development of schisis-like CME through multiple factors, including tractional force, vascular endothelial growth factors, and inflammation.

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“…In mice, the protein is first observed around postnatal day six (P6), and adult expression patterning is reached at P12 [18]. In the mature retina only PRs and bipolar cells are involved in RS1 synthesis, subsequently, in its secretion [18,33,34]. As a consequence, RS1 is detected throughout the inner and outer mature retina as a secreted protein ( [18,35].…”

Section: Localizationmentioning

confidence: 99%

“…Gene delivery for treating XLRS should be focused on the outer retina, specifically the photoreceptors, and in the inner retina targeting bipolar cells, since they are involved in RS1 synthesis in the mature retina [18,33,34]. Transduction of RS1 in photoreceptors of a Rs1h-deficient mouse model showed significant improvements in RS1 production and secretion and a reduced the number of cavities, improved retinal organization and led to functional rescue [54].…”

Section: Adeno-associated Viral Vector-mediated Gene Augmentation The...mentioning

confidence: 99%

“…Thirdly, there was AAV2/4, a recombinant subtype of AAV2 that particularly transduces photoreceptors [91]. Fourthly, rAAV2.2-Y444F was used, which is a rAAV2 serotype 2 with a single mutation (Y444F) on the capsid [34]. One group used AAVshH10, which is derived from the AAV6 shuffled library and primarily targets Müller cells [92].…”

Section: Therapy Characteristicsmentioning

confidence: 99%

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The Road towards Gene Therapy for X-Linked Juvenile Retinoschisis: A Systematic Review of Preclinical Gene Therapy in Cell-Based and Rodent Models of XLRS

van der Veen,

Heredero Berzal,

Koster

et al. 2024

IJMS

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X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with formation of cystoid retinal cavities, frequently accompanied by splitting of the retinal layers, impaired synaptic transmission of visual signals, and associated loss of visual acuity. XLRS is caused by loss-of-function mutations in the retinoschisin gene located on the X chromosome (RS1, MIM 30083). While proof-of-concept studies for gene augmentation therapy have been promising in in vitro and rodent models, clinical trials in XLRS patients have not been successful thus far. We performed a systematic literature investigation using search strings related to XLRS and gene therapy in in vivo and in vitro models. Three rounds of screening (title/abstract, full text and qualitative) were performed by two independent reviewers until consensus was reached. Characteristics related to study design and intervention were extracted from all studies. Results were divided into studies using (1) viral and (2) non-viral therapies. All in vivo rodent studies that used viral vectors were assessed for quality and risk of bias using the SYRCLE’s risk-of-bias tool. Studies using alternative and non-viral delivery techniques, either in vivo or in vitro, were extracted and reviewed qualitatively, given the diverse and dispersed nature of the information. For in-depth analysis of in vivo studies using viral vectors, outcome data for optical coherence tomography (OCT), immunohistopathology and electroretinography (ERG) were extracted. Meta-analyses were performed on the effect of recombinant adeno-associated viral vector (AAV)-mediated gene augmentation therapies on a- and b-wave amplitude as well as the ratio between b- and a-wave amplitudes (b/a-ratio) extracted from ERG data. Subgroup analyses and meta-regression were performed for model, dose, age at injection, follow-up time point and delivery method. Between-study heterogeneity was assessed with a Chi-square test of homogeneity (I2). We identified 25 studies that target RS1 and met our search string. A total of 19 of these studies reported rodent viral methods in vivo. Six of the 25 studies used non-viral or alternative delivery methods, either in vitro or in vivo. Of these, five studies described non-viral methods and one study described an alternative delivery method. The 19 aforementioned in vivo studies were assessed for risk of bias and quality assessments and showed inconsistency in reporting. This resulted in an unclear risk of bias in most included studies. All 19 studies used AAVs to deliver intact human or murine RS1 in rodent models for XLRS. Meta-analyses of a-wave amplitude, b-wave amplitude, and b/a-ratio showed that, overall, AAV-mediated gene augmentation therapy significantly ameliorated the disease phenotype on these parameters. Subgroup analyses and meta-regression showed significant correlations between b-wave amplitude effect size and dose, although between-study heterogeneity was high. This systematic review reiterates the high potential for gene therapy in XLRS, while highlighting the importance of careful preclinical study design and reporting. The establishment of a systematic approach in these studies is essential to effectively translate this knowledge into novel and improved treatment alternatives.

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Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors

Cited by 5 publications

References 61 publications

Retinal organoids with X-linked retinoschisis RS1 (E72K) mutation exhibit a photoreceptor developmental delay and are rescued by gene augmentation therapy

Retinal organoids with X-linked retinoschisis RS1 (E72K) mutation exhibit a photoreceptor developmental delay and are rescued by gene augmentation therapy

Schisis-like Cystoid Macular Edema in Eyes with Diffuse Laser-treated Scars

The Road towards Gene Therapy for X-Linked Juvenile Retinoschisis: A Systematic Review of Preclinical Gene Therapy in Cell-Based and Rodent Models of XLRS

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