Volume 94, December 2023, 101218Author links open overlay panelAbstract

More than 76 million people worldwide are afflicted with the neurodegenerative eye diseases described and grouped together as glaucoma. A common feature amongst the many forms of glaucoma is chronically elevated intraocular pressure (IOP) within the anterior chamber of the eye that physically damages the retina, optic nerve and parts of the brain connected with visual perception. The mediators of the contusing raised IOP responsible for such damage and loss of vision include locally released inflammatory agents, tissue remodeling enzymes and infiltrating immune cells which damage the retinal ganglion cell (RGC) axons and eventually kill a significant number of the RGCs. Additional culprits include genetic defects of the patient that involve aberrations in receptors, enzymes and/or endogenous ligands and possible over- or under-production of the latter. Other genetic abnormalities may include issues with signal transduction machinery within key cells of critical tissues in the front (e.g. trabecular meshwork [TM] and Schlemm's canal [SC]) and back of the eye (e.g. retinal ganglion cells and their axons). Genome-wide associated studies (GWAS) coupled with next generation sequencing have provided powerful linkage of certain gene defects and polymorphic variants to the onset and progression of diseases of the tissues involved in fluid dynamics in the TM and SC, and many retinal elements (lamina cribosa, optic nerve head) at the back of the eye which cause ocular hypertension (OHT) and glaucomatous optic neuropathy (GON), respectively. Despite the availability of some drugs, fluid drainage microshunts and full surgical techniques to lower and control intraocular pressure, the major modifiable biomarker of open-angle and other forms of glaucoma, their side-effect profiles, less than optimum effectiveness and short duration of action present opportunities to clinically manage the glaucomas with next generation of treatments with high therapeutic indices, including gene therapies. Thus, identification, characterization and deployment of genetic data coupled with traditional drug discovery and novel gene replacement, gene editing and genetic engineering technologies may provide some solutions to the aforementioned problems. These aspects will be discussed in this article.

Section snippetsIntroduction to glaucoma

The debilitating heterogenous eye disorders grouped together as “glaucoma” all result in vision loss and can cause blindness if not timely diagnosed and treated. Glaucoma robs sight of millions of people worldwide (Tham et al., 2014). Despite etiological differences amongst various forms of glaucoma, the most common features and clinically relevant outcomes are the same. Thus, irreversible damage to retinal ganglion cells (RGCs) and their axons, which constitutes the optic nerve, increased

Genetic contributions to OHT/OAG etiology

By way of introduction to the genetic elements, it is now well-accepted that a multitude of human diseases result from abnormalities in genes or chromosomes. Gene mutations are responsible for inherited disorders. Moreover, genetic diseases can result from addition of an extra gene or deletion of a gene, missing gene(s), and/or from translocated or mutated genes. In the eye, genetic disorders detected by genome-wide associated studies (GWAS) (Fig. 3B; Manhattan plot for primary open-angle

High-level overview of gene therapy and its delivery to target tissues

Due to significant progress in genetics and technologies for using genomic information, the deployment of gene therapies has rapidly expanded covering many human diseases. From gene replacement to controlling expression of the gene product to modification of specific ligand molecule delivery or capture over an extended period of time, gene therapies are providing novel ways to treat ocular diseases beyond traditional small molecule drugs or antibodies. Furthermore, gene therapies permit local

Genetic studies and linkage to low or non-responding patients

The genetic variability amongst humans dictates the relative efficacy and the side-effect profiles of drugs and various disease-related therapeutics. Identifying patients that may respond poorly to treatments for eye diseases, in particular OHT/POAG has relied on GWAS as well. This is important knowledge to aid in prescribing the appropriate medication, and such information can be valuable in selecting patients for prospective clinical trials of new drugs with similar mechanisms of action to

Gene therapy for OHT/POAG

Notable advances in the effectiveness of gene therapies for numerous human diseases has catalyzed the advent and deployment of similar therapies for eye diseases. A few key examples related to treatment of OHT/POAG are worth highlighting, even though mainly animal data exist and only a very small number have been translated in the clinical setting.

As noted in various sub-sections above, occlusion of the TM/SC by aberrantly deposited collagens and fibronectins, and their non-clearance by absent

Summary and concluding remarks

Glaucoma represents a constellation of diseases linked with slow but progressive loss of RGCs and their axons within the optic nerve resulting in degradation and loss of the visual field. Along with its traumatic and devastating negative impact on the patients' quality of life, GON inflicts an ever-increasing socioeconomic burden globally on communities. Hence, there continues to be an unmet medical need for novel and transformative treatment options for patients with OHT and glaucoma,

Declaration of competing interest

The author declares no conflict of interest. His only aim is to promote sharing of knowledge and to help young scientists better understand the landscape of etiology and treatments for ocular hypertension and various types of glaucoma. This in turn will hopefully inspire other scientists to perform rigorous and productive research in these areas to help patients with new treatment options for these ocular diseases in the future.

Acknowledgements

I'm indebted to my colleagues in the ophthalmic industry, academia and my family members for inspiring me to keep learning, gathering information and disseminating it to others. Together we can help solve health problems for those who are less fortunate than us.

References (137)A.M. Maguire et al.Durability of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease: phase 3 results at 3 and 4 years

Ophthalmology

(2021)

T. Martínez et al.In vitro and in vivo efficacy of SYL040012, a novel siRNA compound for treatment of glaucoma

Mol. Ther.

(2014)

J. Moreno-Montañés et al.Phase I clinical trial of SYL040012, a small interfering RNA targeting β-adrenergic receptor 2, for lowering intraocular pressure

Mol. Ther.

(2014)

M.T. Pardue et al.Neuroprotective strategies for retinal disease

Prog. Retin. Eye Res.

(2018)

A. Qassim et al.An intraocular pressure polygenic risk score stratifies multiple primary open-angle glaucoma parameters including treatment intensity

Ophthalmol. Times

(2020)

Y. Sakurada et al.Genetics of primary open-angle glaucoma and its endophenotypes

Prog. Brain Res.

(2020)

M. Sakurai et al.Association between genetic polymorphisms of the prostaglandin F2alpha receptor gene and response to latanoprost

Ophthalmology

(2007)

N.A. SharifDegeneration of retina-brain components and connections in glaucoma: disease causation and treatment options for eyesight preservation

Curr. Res. Neurobiol.

(2022)

N.A. SharifIdentifying new drugs and targets to treat rapidly elevated intraocular pressure for angle closure and secondary glaucomas to curb visual impairment and prevent blindness

Exp. Eye Res.

(2023)

T.S. Acott et al.Normal and glaucomatous outflow regulation

Prog. Retin. Eye Res.

(2020)

I.F. Aboobakar et al.Rare protective variants and glaucoma-relevant cell stressors modulate angiopoietin-like 7 expression

Hum. Mol. Genet.

(2023)

M. Aga et al.Differential effects of caveolin-1 and -2 knockdown on aqueous outflow and altered extracellular matrix turnover in caveolin-silenced trabecular meshwork cells

Invest. Ophthalmol. Vis. Sci.

(2014)

W.L. Alward et al.Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A)

N. Engl. J. Med.

(1998)

C. Amador et al.Gene therapy in the anterior eye segment

Curr. Gene Ther.

(2022)

M.V.R. Araki et al.Association of ABCA1 (rs2472493) and GAS7 (rs9913911) gene variants with primary open-angle glaucoma in a Brazilian population

Mol. Vis.

(2022)

J. Arcuri et al.Ocular treatments targeting separate prostaglandin receptors in mice exhibit alterations in intraocular pressure and optic nerve lipidome

J. Ocul. Pharmacol. Therapeut.

(2023)

N.G. Asefa et al.Bioinformatic prioritization and functional annotation of GWAS-based candidate genes for primary open-angle glaucoma

Genes

(2022)

T. Aung et al.Glaucoma genetics: recent advances and future directions

Asia Pac J. Ophthalmol.

(2016)

T. Aung et al.A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene

Hum. Genet.

(2002)

T. Aung et al.Molecular analysis of the myocilin gene in Chinese subjects with chronic primary-angle closure glaucoma

Invest. Ophthalmol. Vis. Sci.

(2005)

T. Aung et al.Genetics of exfoliation syndrome

J. Glaucoma

(2018)

J.N. Bailey et al.Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Nat. Genet.

(2016)

S. Batabyal et al.Sensitization of ON-bipolar cells with ambient light activatable multi-characteristic opsin rescues vision in mice

Gene Ther.

(2021)

D. Berner et al.The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome

Hum. Mol. Genet.

(2019)

T. BorrásThe pathway from genes to gene therapy in glaucoma: a review of possibilities for using genes as glaucoma drugs

Asia Pac J. Ophthalmol.

(2017)

C. Bucolo et al.Novel therapeutics in glaucoma management

Curr. Neuropharmacol.

(2018)

K.P. Burdon et al.Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

Nat. Genet.

(2011)

D.J. Calkins et al.The cell and molecular biology of glaucoma: axonopathy and the brain

Invest. Ophthalmol. Vis. Sci.

(2012)

M.I. Canut et al.MLIP genotype as a predictor of pharmacological response in primary open-angle glaucoma and ocular hypertension

Sci. Rep.

(2021)

O.F. Chacon-Camacho et al.Review and update on the molecular basis of Leber congenital amaurosis

World J. Clin. Cases

(2015)

X. Chai et al.Association of glaucoma risk genes with retinal nerve fiber layer in a multi-ethnic Asian population: the Singapore epidemiology of eye diseases study

Invest. Ophthalmol. Vis. Sci.

(2020)

Y. Chen et al.Common variants near ABCA1 and in PMM2 are associated with primary open-angle glaucoma

Nat. Genet.

(2014)

S.R. Chintalapudi et al.NEIGHBORHOOD consortium; International Glaucoma Genetics consortium, et al. Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

Nat. Commun.

(2017)

H. Choquet et al.A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure

Nat. Commun.

(2017)

A. Dibas et al.Engineered mechanosensitive channel as outflow actuator for gene agnostic gene therapy of glaucoma

ARVO

(2023)

R.J. Donahue et al.BCLXL gene therapy moderates neuropathology in the DBA/2J mouse model of inherited glaucoma

Cell Death Dis.

(2021)

L.P. Doucette et al.FOXC1 Regulates Expression of prostaglandin receptors leading to an attenuated response to latanoprost

Invest. Ophthalmol. Vis. Sci.

(2018)

R. Gerometta et al.Treatment of sheep steroid-induced ocular hypertension with a glucocorticoid-inducible MMP1 gene therapy virus

Invest. Ophthalmol. Vis. Sci.

(2010)

P. Gharahkhani et al.Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Nat. Commun.

(2021)

A. Guinart et al.Synthetic molecular motor activates drug delivery from polymersomes

Proc. Natl. Acad. Sci. U. S. A.

(2023)

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