Animal Models of Glaucoma

Johnson, Thomas V.; Tomarev, Stanislav I.

doi:10.1007/978-3-319-19434-9_3

Cited by 4 publications

(9 citation statements)

References 147 publications

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“…Rodent models have been widely used in glaucoma research and have provided invaluable insights into the pathogenesis, genetics, and treatment of human disease. A complete discussion of all available models is beyond the scope of this manuscript (and has been the subject of excellent recent reviews, including Fernandes et al 23 and Johnson et al 24 ), but contextualizing our results in relation to some existing models will aid in evaluating the utility of Angpt1 ΔWB mice in the study of glaucoma.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin-1 Knockout Mice as a Genetic Model of Open-Angle Glaucoma

Thomson

Grannonico

Liu

et al. 2020

Trans. Vis. Sci. Tech.

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A leading cause of blindness worldwide, glaucoma is often caused by elevated intraocular pressure (IOP) due to impaired aqueous humor outflow from the anterior chamber through Schlemm's canal (SC) and the trabecular meshwork. Despite the large clinical burden, glaucoma research and drug development are hindered by a limited selection of preclinical models that accurately recapitulate human disease. Here, we propose that Angpt1 conditional knockout mice may provide one such model. Angiopoietin/TEK (ANGPT/TEK) signaling is crucial for SC formation and integrity in mice and humans, and mice lacking TEK or its ligand ANGPT1 develop a hypomorphic SC insufficient for normal aqueous humor outflow. Methods: We used a comprehensive histology and physiology approach to characterize the glaucoma phenotype of Angpt1 inducible knockout mice, especially focusing on retina morphology and function. Results: Angpt1 deletion resulted in persistent ocular hypertension beginning in the first month after birth and leading to decreased visual acuity with age due to glaucomatous neuropathy. In the neural retina, we identified marked and specific loss of the retinal ganglion cells, whereas other retinal neurons exhibited largely normal morphology and patterning. Electroretinogram recordings demonstrated reduced scotopic threshold response, further indicating loss of retinal ganglion cell function. Conclusions: These findings highlight the potential of Angpt1 conditional knockout mice as a valuable new glaucoma model. Translational Relevance: Currently, few reliable, rapid-onset genetic glaucoma models are available, and Angpt1 knockout mice will provide an additional tool for studies of IOP-induced neural damage, mechanisms of disease progression, and novel treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Angiopoietin-1 Knockout Mice as a Genetic Model of Open-Angle Glaucoma

Thomson

Grannonico

Liu

et al. 2020

Trans. Vis. Sci. Tech.

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“…51 Genetic backgrounds vary among the mice used to generate the currently available myocilin glaucoma mouse models and could modulate phenotype severity. 10,51 Notably, adenovirusinduced overexpression of human Tyr437His myocilin resulted in an elevated IOP in A/J, BALB/cJ, and C57BL/6J mice, but not in C3H/HeJ mice. 52 Finally, mutant myocilin expression levels may influence resultant phenotypes.…”

Section: ■ Discussionmentioning

confidence: 98%

“…In the case of myocilin, nonsynonymous mutations in Hs OLF result in a non-native protein that recruits properly folded myocilin into a template-assisted amyloid aggregation process, , leading to cell stress and death. − In vitro , modifying parameters such as elevated temperature, low pH, slow agitation, and redox manipulation also access a partially folded state of wild-type Hs OLF, which in turn facilitates fibrilization. , Other animals with a similar eye anatomy to humans and mutations in the myocilin gene (e.g., monkey) do not develop glaucoma, and robust phenotypes are not readily induced in mice, , prompting us to consider the possibility that myocilin homologues exhibit biophysical features that protect against aggregation or facilitate cellular degradation of aggregates.…”

Section: Discussionmentioning

confidence: 99%

“…7,8 Data to date indicate that myocilin is not otherwise a susceptibility gene for sporadic forms of glaucoma. 9 Numerous glaucoma rodent models are available and widely used in the field, 10 but for myocilin-associated glaucoma, a robust IOP elevation phenotype accompanied by RGC loss has been a challenge to elicit in mice. In two mouse models that express either the human Tyr437His myocilin mutation 11 or its equivalent in Mus musculus myocilin (Uniprot O70624), Tyr423His, 12 a modest IOP elevation was measured, 11,12 but only in older mice.…”

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confidence: 99%

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Differential Misfolding Properties of Glaucoma-Associated Olfactomedin Domains from Humans and Mice

et al. 2019

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Mutations in myocilin, predominantly within its olfactomedin (OLF) domain, are causative for the heritable form of open angle glaucoma in humans. Surprisingly, mice expressing Tyr423His mutant myocilin, corresponding to a severe glaucoma-causing mutation (Tyr437His) in human subjects, exhibit a weak, if any, glaucoma phenotype. To address possible protein-level discrepancies between mouse and human OLFs, which might lead to this outcome, biophysical properties of mouse OLF were characterized for comparison with those of human OLF. The 1.55 Å resolution crystal structure of mouse myocilin OLF reveals an asymmetric 5-bladed β-propeller that is nearly indistinguishable from previous structures of human OLF. Wild type and selected mutant mouse OLFs mirror thermal stabilities of their human OLF counterparts, including characteristic stabilization in the presence of calcium. Mouse OLF forms thioflavin T-positive aggregates with similar end-point morphology as human OLF, but amyloid aggregation kinetic rates of mouse OLF are faster than human OLF. Simulations and experiments support the interpretation that kinetics of mouse OLF are faster because of decreased charge repulsion arising from more neutral surface electrostatics. Taken together, phenotypic differences observed in mouse and human studies of mutant myocilin could be a function of aggregation kinetics rates, which would alter the lifetime of putatively protofibrillar intermediates.

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“…Congenital glaucoma types include autosomal recessive mutations in CYP1B1 (cytochrome P450 family 1 subfamily B polypeptide 1) and LTBP2 (Latenttransforming growth factor beta-binding protein), and autosomal dominant mutations in MYOC (myocilin), OPTN (optineurin), and WDR36 (WD repeat-containing protein 36) [5]. Another study adds that the transcription factors FOXC1 (Forkhead box C1), FOXC2 (Forkhead box C2), PITX2 (Paired Like Homeodomain 2), LMX1B (LIM homeobox transcription factor 1 beta), and PAX6 (Paired box protein) contribute to congenital glaucoma [34].…”

Section: Primary Congenital Glaucomamentioning

confidence: 99%

An Overview of Glaucoma: Bidirectional Translation between Humans and Pre-Clinical Animal Models

Pilkinton¹,

Hollingsworth²,

Jerkins³

et al. 2022

Preclinical Animal Modeling in Medicine

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Glaucoma is a multifactorial, polygenetic disease with a shared outcome of loss of retinal ganglion cells and their axons, which ultimately results in blindness. The most common risk factor of this disease is elevated intraocular pressure (IOP), although many glaucoma patients have IOPs within the normal physiological range. Throughout disease progression, glial cells in the optic nerve head respond to glaucomatous changes, resulting in glial scar formation as a reaction to injury. This chapter overviews glaucoma as it affects humans and the quest to generate animal models of glaucoma so that we can better understand the pathophysiology of this disease and develop targeted therapies to slow or reverse glaucomatous damage. This chapter then reviews treatment modalities of glaucoma. Revealed herein is the lack of non-IOP-related modalities in the treatment of glaucoma. This finding supports the use of animal models in understanding the development of glaucoma pathophysiology and treatments.

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Animal Models of Glaucoma

Cited by 4 publications

References 147 publications

Angiopoietin-1 Knockout Mice as a Genetic Model of Open-Angle Glaucoma

Angiopoietin-1 Knockout Mice as a Genetic Model of Open-Angle Glaucoma

Differential Misfolding Properties of Glaucoma-Associated Olfactomedin Domains from Humans and Mice

An Overview of Glaucoma: Bidirectional Translation between Humans and Pre-Clinical Animal Models

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