Gene Therapy for Glaucoma by Ciliary Body Aquaporin 1 Disruption Using CRISPR-Cas9

Wu, Jiahui; Bell, Oliver H.; Copland, David A; Young, Alison; Pooley, John R.; Maswood, Ryea; Evans, Rachel S; Khaw, PT; Ali, Robin R.; Dick, Andrew D.; Chu, Colin J

doi:10.1016/j.ymthe.2019.12.012

Cited by 64 publications

(45 citation statements)

References 57 publications

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“…The eye is an ideal organ for gene therapy because of the relative ease of access and compartmentalization, relative immune privilege, and small size reducing the viral load required. Unsurprisingly, the use of ocular gene therapy has been successful in a variety of ocular diseases [ 14 , 15 ]. These include gene therapy trials for inherited retinal degenerations, such as Leber congenital amaurosis (LCA), retinitis pigmentosa, choroideremia, and X-linked retinoschisis (XLRS) [ 14 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

Lee

Lin

Copland

et al. 2021

J Neuroinflammation

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Age-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed “chronic” senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

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Section: Introductionmentioning

confidence: 99%

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

Lee

Lin

Copland

et al. 2021

J Neuroinflammation

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“… 54 Second, disruption of AQP1 via CRISPR-Cas9 in the ciliary body resulted in reduced IOP in mouse models. 55 Moreover, AQPs are known to modulate the gap junction proteins, connexins, 56 and Cx43 in particular has been shown to be critical for the integrity of the posterior pigmented epithelium/ myoepithelium junction, as well as aqueous humor production and IOP regulation. 57 , 58 Although specific interaction between AQP1 (or AQP2) and Cx43 in the iris has not yet been reported, we predict that upregulation of AQP1 may influence Cx43 expression.…”

Section: Discussionmentioning

confidence: 99%

Altered Iris Aquaporin Expression and Aqueous Humor Osmolality in Glaucoma

Huang

Seet

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Purpose Aquaporins (AQPs) facilitate transmembrane osmotic water transport and may play a role in iris fluid conductivity, which is implicated in the pathophysiology of glaucoma. In this study, we compared the iris expression of AQPs and aqueous osmolality between primary angle closure glaucoma (PACG), primary open-angle glaucoma (POAG), and nonglaucoma eyes. Methods AQP1-5 transcripts from a cohort of 36 PACG, 34 POAG and 26 nonglaucoma irises were measured by quantitative real-time PCR. Osmolality of aqueous humor from another cohort of 49 PACG, 50 POAG, and 50 nonglaucoma eyes were measured using an osmometer. The localization of AQP1 in both glaucoma and nonglaucoma irises was determined by immunofluorescent analysis. Results Of the five AQP genes evaluated, AQP1 and AQP2 transcripts were significantly upregulated in both PACG (3.48- and 8.07-fold, respectively) and POAG (3.12- and 11.58-fold, respectively) irises relative to nonglaucoma counterparts. The aqueous osmolalities of PACG (303.68 mmol/kg) and POAG (300.79 mmol/kg) eyes were significantly lower compared to nonglaucoma eyes (312.6 mmol/kg). There was no significant difference in expression of AQP transcripts or aqueous osmolality between PACG and POAG eyes. Conclusions PACG and POAG eyes featured significant increase in AQP1 and AQP2 expression in the iris and reduced aqueous osmolality compared to nonglaucoma eyes. These findings suggest that the iris may be involved in altered aqueous humor dynamics in glaucoma pathophysiology. Because PACG did not differ from POAG in both properties studied, it is likely that they are common to glaucoma disease in general.

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“…The ciliary body epithelium can be reached by gene therapy vectors via intravitreal injection (Figures 2 and 3). 94,117 Recently, a team of investigators achieved a reduction of aqueous humor production in experimental mouse models of corticosteroid and microbead‐induced ocular hypertension following an intravitreal AAV administration that resulted in disruption of the aquaporin 1 ( AQP1 ) gene within the ciliary epithelium by use of CRISPR‐Cas9 gene editing 117 …”

Section: Intraocular Pressure (Iop) Controlmentioning

confidence: 99%

Looking into the future: Gene and cell therapies for glaucoma

Komàromy

Koehl

Park

2021

Veterinary Ophthalmology

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Glaucoma is a complex group of optic neuropathies that affects both humans and animals. Intraocular pressure (IOP) elevation is a major risk factor that results in the loss of retinal ganglion cells (RGCs) and their axons. Currently, lowering IOP by medical and surgical methods is the only approved treatment for primary glaucoma, but there is no cure, and vision loss often progresses despite therapy. Recent technologic advances provide us with a better understanding of disease mechanisms and risk factors; this will permit earlier diagnosis of glaucoma and initiation of therapy sooner and more effectively. Gene and cell therapies are well suited to target these mechanisms specifically with the potential to achieve a lasting therapeutic effect. Much progress has been made in laboratory settings to develop these novel therapies for the eye. Gene and cell therapies have already been translated into clinical application for some inherited retinal dystrophies and age‐related macular degeneration (AMD). Except for the intravitreal application of ciliary neurotrophic factor (CNTF) by encapsulated cell technology for RGC neuroprotection, there has been no other clinical translation of gene and cell therapies for glaucoma so far. Possible application of gene and cell therapies consists of long‐term IOP control via increased aqueous humor drainage, including inhibition of fibrosis following filtration surgery, RGC neuroprotection and neuroregeneration, modification of ocular biomechanics for improved IOP tolerance, and inhibition of inflammation and neovascularization to prevent the development of some forms of secondary glaucoma.

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Gene Therapy for Glaucoma by Ciliary Body Aquaporin 1 Disruption Using CRISPR-Cas9

Cited by 64 publications

References 57 publications

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

Altered Iris Aquaporin Expression and Aqueous Humor Osmolality in Glaucoma

Looking into the future: Gene and cell therapies for glaucoma

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