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Updated: Jul 9, 2025
Induction of Ocular Surface Inflammation and Collection of Involved Tissues
Published on: August 4, 2022
Distinct mouse models of Stargardt disease display differences in pharmacological targeting of ceramides and
Zachary J Engfer1,2, Dominik Lewandowski1, Zhiqian Dong1
1Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, CA 92697.
Abstract:
Mutations in many visual cycle enzymes in photoreceptors and retinal pigment epithelium (RPE) cells can lead to the chronic accumulation of toxic retinoid byproducts, which poison photoreceptors and the underlying RPE if left unchecked. Without a functional ATP-binding cassette, sub-family A, member 4 (ABCA4), there is an elevation of all-trans-retinal and prolonged buildup of all-trans-retinal adducts, resulting in a retinal degenerative disease known as Stargardt-1 disease. Even in this monogenic disorder, there is significant heterogeneity in the time to onset of symptoms among patients. Using a combination of molecular techniques, we studied Abca4 knockout (simulating human noncoding disease variants) and Abca4 knock-in mice (simulating human misfolded, catalytically inactive protein variants), which serve as models for Stargardt-1 disease. We compared the two strains to ascertain whether they exhibit differential responses to agents that affect cytokine signaling and/or ceramide metabolism, as alterations in either of these pathways can exacerbate retinal degenerative phenotypes. We found different degrees of responsiveness to maraviroc, a known immunomodulatory CCR5 antagonist, and to the ceramide-lowering agent AdipoRon, an agonist of the ADIPOR1 and ADIPOR2 receptors. The two strains also display different degrees of transcriptional deviation from matched WT controls. Our phenotypic comparison of the two distinct Abca4 mutant-mouse models sheds light on potential therapeutic avenues previously unexplored in the treatment of Stargardt disease and provides a surrogate assay for assessing the effectiveness for genome editing.
Insights
Mutations in the ABCA4 gene cause Stargardt disease by accumulating toxic retinoids. Mouse models revealed differential responses to potential therapies, offering new insights for treating this retinal degenerative disease.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- Mutations in visual cycle enzymes, particularly ABCA4, lead to toxic retinoid byproduct accumulation in photoreceptors and retinal pigment epithelium (RPE).
- This accumulation causes retinal degeneration, exemplified by Stargardt disease, a condition with variable symptom onset.
- ATP-binding cassette, sub-family A, member 4 (ABCA4) dysfunction results in elevated all-trans-retinal and its adducts, driving retinal pathology.
Purpose of the Study:
- To compare the responses of two distinct mouse models of Stargardt disease (Abca4 knockout and knock-in) to therapeutic agents.
- To investigate whether cytokine signaling and ceramide metabolism pathways influence disease progression in these models.
- To evaluate the utility of these models for assessing potential Stargardt disease treatments and genome editing efficacy.
Main Methods:
- Utilized Abca4 knockout mice (simulating noncoding variants) and Abca4 knock-in mice (simulating inactive protein variants) as models for Stargardt disease.
- Administered maraviroc (CCR5 antagonist) and AdipoRon (ceramide-lowering agent) to assess differential responses.
- Analyzed transcriptional changes in mutant mouse strains compared to wild-type (WT) controls.
Main Results:
- The Abca4 knockout and knock-in mouse models exhibited varying degrees of responsiveness to maraviroc and AdipoRon.
- Significant differences in transcriptional profiles were observed between the two mutant strains and WT controls.
- The study identified differential therapeutic responses, highlighting distinct disease mechanisms in the models.
Conclusions:
- Phenotypic comparison of distinct Abca4 mutant mouse models provides insights into unexplored therapeutic avenues for Stargardt disease.
- These models serve as valuable tools for evaluating the efficacy of novel treatments, including genome editing strategies.
- Understanding differential responses to immunomodulatory and metabolic agents can guide future Stargardt disease therapeutic development.
