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Updated: Jun 17, 2025
Regenerative Therapy by Suprachoroidal Cell Autograft in Dry Age-related Macular Degeneration: Preliminary In Vivo Report
Published on: February 12, 2018
GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology
Sophia M DiCesare1, Antonio J Ortega2, Gracen E Collier1
1Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Abstract:
Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) is an age-related macular degeneration-like (AMD-like) retinal dystrophy caused by an autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3). To identify new small molecules that reduce F3 production in retinal pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into the endogenous F3 locus that enabled simple, sensitive, and high-throughput detection of the protein. The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced F3 burden (expression, secretion, and intracellular levels) in immortalized RPE and non-RPE cells. Low-level, long-term CHIR treatment promoted remodeling of the RPE extracellular matrix, reducing sub-RPE deposit-associated proteins (e.g., amelotin, complement component 3, collagen IV, and fibronectin), while increasing RPE differentiation factors (e.g., tyrosinase, and pigment epithelium-derived factor). In vivo, treatment of 8-month-old R345W+/+ knockin mice with CHIR (25 mg/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size, thereby preventing the main pathological feature in these mice. This is an important demonstration of small molecule-based prevention of AMD-like pathology in ML/DHRD mice and may herald a rejuvenation of interest in GSK3 inhibition for the treatment of retinal degenerative diseases, including potentially AMD itself.
Insights
GSK3 inhibitor CHIR99021 reduced fibulin-3 production in retinal cells, preventing age-related macular degeneration-like pathology in mice. This suggests potential for GSK3 inhibition in treating retinal degenerative diseases.
Area of Science:
- Ophthalmology
- Genetics
- Pharmacology
Background:
- Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) is an inherited retinal dystrophy resembling age-related macular degeneration (AMD).
- It is caused by a specific mutation (R345W) in the fibulin-3 (F3) gene, leading to F3 protein accumulation.
- Current treatments for such conditions are limited, necessitating novel therapeutic strategies.
Purpose of the Study:
- To discover small molecules that decrease fibulin-3 production in retinal cells.
- To evaluate the therapeutic potential of identified compounds in a mouse model of ML/DHRD.
Main Methods:
- Developed a high-throughput screening method using a luminescent tag (HiBiT) in the endogenous F3 gene locus.
- Tested the GSK3 inhibitor CHIR99021 (CHIR) in immortalized retinal pigmented epithelium (RPE) and non-RPE cells.
- Administered CHIR to a mouse model (R345W+/+ knockin mice) exhibiting AMD-like pathology.
Main Results:
- CHIR significantly reduced F3 expression, secretion, and intracellular levels in cell cultures.
- Long-term CHIR treatment led to RPE extracellular matrix remodeling and increased RPE differentiation markers.
- In vivo, CHIR treatment effectively reduced basal laminar deposits in ML/DHRD mice, preventing key pathological features.
Conclusions:
- CHIR99021 demonstrates efficacy in reducing F3 burden and preventing AMD-like pathology in a relevant mouse model.
- This study highlights the potential of small molecule-based approaches, specifically GSK3 inhibition, for treating retinal degenerative diseases like ML/DHRD and potentially AMD.
- Further research into GSK3 inhibitors may offer new therapeutic avenues for patients with inherited retinal dystrophies.
