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Retinal Development and Disorders / Genetic and Kidney Cyst Diseases · Journal article
Advanced Science · September 9, 2026
Early or partial results. Treat as a signal, not a conclusion.
This is a feasibility study in patient-derived iPSC trabecular meshwork cells showing that both AAV2-OCRL augmentation and CRISPR-mediated OCRL correction can restore enzyme activity and reverse cellular defects in vitro. The work identifies ECM-adhesion-cytoskeletal pathway dysregulation as a potential mechanism of trabecular meshwork dysfunction in Lowe syndrome, but provides no evidence of in vivo efficacy or translation to human disease.
In vitro mechanistic proof-of-concept study. Trabecular meshwork cells derived from iPSCs generated from Lowe syndrome patients.. Intervention: AAV2-OCRL gene augmentation therapy and patient-specific CRISPR-mediated OCRL gene correction.. Compared with: Patient-derived iPSC trabecular meshwork models without gene therapy intervention (implied)..
AAV2-OCRL showed highest transduction efficiency among three AAV-OCRL vectors tested in patient iPSC-derived trabecular meshwork models. CRISPR-based gene therapy restored OCRL enzyme activity and corrected cellular defects in patient-derived models. RNA-sequencing revealed dysregulation of extracellular matrix organization, cell adhesion, focal adhesion, and cytoskeletal regulatory pathways in Lowe syndrome models.
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In vitro proof-of-concept in iPSC-derived cell models demonstrating feasibility of two gene therapy approaches, without in vivo efficacy, clinical outcomes, or animal validation.
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Lowe syndrome is a rare, currently incurable multisystem disorder that affects the eyes, kidneys, and central nervous system. It is caused by mutations in the OCRL gene, which encodes an inositol 5-phosphatase. The disorder remains incurable, and the pathways underlying the ocular symptoms remain poorly understood, largely due to the lack of appropriate models. In this study, trabecular meshwork cell models of Lowe syndrome were generated to test two distinct gene therapy strategies: a mutation-agnostic OCRL DNA augmentation therapy and a patient-specific CRISPR-mediated gene correction strategy. The results showed that AAV2-OCRL demonstrated the highest transduction efficiency in patient iPSC-derived trabecular meshwork models (iHTM) among the three AAV-OCRL vectors evaluated, establishing it as a promising delivery vector. Targeted CRISPR-based gene therapy restored OCRL enzyme activity and corrected cellular defects in patient iPSC-derived trabecular meshwork cell models. Furthermore, RNA-sequencing analysis of these models revealed dysregulation of extracellular matrix organization, cell adhesion, focal adhesion, and cytoskeletal regulatory pathways, suggesting that disruption of interconnected ECM-adhesion-cytoskeletal networks may contribute to trabecular meshwork dysfunction in Lowe syndrome-associated glaucoma. These findings indicate the feasibility of OCRL gene augmentation and CRISPR-based gene editing in patient-derived ocular models and position AAV2-OCRL as a leading therapeutic candidate for Lowe syndrome.
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