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Salma Hassan thesis 2025-corrections complete6.69 MB
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Dissertation
Developing novel treatments for X-linked retinoschisis (XLRS)
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2025
DOI: 10.25820/etd.008233
Abstract
X-linked retinoschisis (XLRS) is a juvenile-onset inherited retinal disorder caused by mutations in the RS1 gene, which encodes retinoschisin, a protein critical for maintaining retinal structural integrity and synaptic organization. This thesis investigates multiple therapeutic strategies in the retinoschisin-knockout (Rs1-KO) mouse model to evaluate the efficacy, durability, and mechanistic underpinnings of gene-based and non-gene-based interventions for XLRS.
In a recent study by our lab, - dose-response study using subretinal delivery of rAAV2tYF-CB-hRS1, we showed that a dose of 8×10 vg/eye produced optimal therapeutic benefit, resulting in significant structural rescue (reduction in cystic schisis) and functional recovery of retinal cells and vision, as measured by electroretinography (ERG) and a functional assay—the visually guided swim assay (VGSA). VGSA was validated as a sensitive, translational endpoint reflecting functional vision under scotopic (low light) and photopic (bright light) conditions, aligning with human mobility-based tests such as the multiluminance mobility test (MLMT) and showing superior sensitivity to ERG.
To evaluate the role of host immunity, Rs1-KO mice were crossed with Rag1-KO mice (lacking adaptive immunity) to generate immunodeficient Rag1-Rs1-DKO mice. Both SKO and DKO groups showed improved ERG responses following gene therapy, with no significant differences in overall amplitudes. However, SKO mice exhibited greater variability and a trend toward early decline, while DKO mice maintained more stable responses. These findings suggest that adaptive immune components may not drive overall therapeutic decline but could contribute to variability in response.
Interestingly, in sham-treated mouse eyes receiving hypertonic buffer alone, we saw schisis resolution and enhanced cone-mediated function, suggesting transient osmotic stabilization of the retinal architecture. Both subretinal and intravitreal buffer injections significantly improved photopic ERG responses.
As another surprising phenomenon elucidated during these studies, we found that light exposure and dark exposure affects the retinas of Rs1-KO mice differently. Contrary to expectations, constant darkness exacerbated structural and functional deficits, while extended light exposure was associated with better structural and functional retinal preservation (Cyst formation was reduced and ERG responses were better).
Collectively, this work highlights the value of combining structural, electrophysiological, functional, and immunological assessments to comprehensively evaluate therapeutic outcomes in XLRS. It underscores the promise of subretinal gene therapy, and the surprising impact of non-genetic environmental factors. These insights inform future translational strategies and support a multimodal approach to therapy for inherited retinal diseases.
Details
- Title: Subtitle
- Developing novel treatments for X-linked retinoschisis (XLRS)
- Creators
- Salma Hassan
- Contributors
- Arlene V. Drack (Advisor)Charles Yeaman (Committee Member)Lori Wallrath (Committee Member)Eric Van Otterloo (Committee Member)Michael Anderson (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Cell and Developmental Biology)
- Date degree season
- Autumn 2025
- DOI
- 10.25820/etd.008233
- Publisher
- University of Iowa
- Number of pages
- xx, 233 pages
- Copyright
- Copyright 2025 Salma Hassan
- Language
- English
- Date submitted
- 10/30/2025
- Description illustrations
- Illustrations, graphs, charts, tables
- Description bibliographic
- Includes bibliographical references (pages 211-233).
- Public Abstract (ETD)
X-linked retinoschisis (XLRS) is a genetic eye disease that mostly affects boys and causes the layers of the retina the light-sensitive tissue at the back of the eye to separate and form fluid containing cysts leading to vision loss. There is currently no approved treatment for XLRS. This thesis tests possible new treatments and investigates how the disease affects vision, using a mouse model that mimics the human disease.
The first treatment of the mouse model involved subretinal gene therapy, which delivers a healthy copy of the abnormal gene directly into the eye. We standardized a functional vision test based on swimming to measure real-world vision in mice more accurately than standard lab tests. Using this and other techniques, we found that a specific dose of subretinal gene therapy improved the animals ability to see. This treatment is under review to move to human clinical trials. We also investigated how the animals immune system affects both the disease and the outcome of gene therapy.
Unexpectedly, we found that even a simple hypertonic salt solution injected into the eye can improve cysts and vision in mice with XLRS. Finally, we explored the effects of standard fluorescent lighting on the structure and function of the retinas in these mice. We found that mice living in constant light had complete resolution of the retinal cysts, suggesting that controlled light exposure may be a treatment for people with XLRS.
Together, these findings bring us closer to safe and effective treatments for XLRS, while offering new tools to test therapies in meaningful ways.
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9985135348502771
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