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  • Review Article
  • Published:

Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma

Nature Reviews Drug Discovery volume 11, pages 541–559 (2012)Cite this article

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This article has been updated

Key Points

  • Blindness affects millions of people worldwide. The leading causes of irreversible visual impairment include age-related macular degeneration (AMD), retinal vascular diseases and glaucoma.

  • During the past decade there have been substantial advances in our understanding of the pathogenesis and genetics of ophthalmic diseases, and the extent of treatable conditions and treatment options continues to increase.

  • Intravitreal injection of anti-angiogenic agents has emerged as the most effective therapy for AMD and retinal vascular diseases. Clinical trials are underway to evaluate new drugs directed against several novel targets in the complement system and angiogenic pathways for the treatment of AMD, and neuroprotective drugs are being investigated for the treatment of both AMD and glaucoma. Other promising therapeutics include gene therapy and stem cell therapy.

  • However, there are still no effective therapies for several common disorders that cause blindness, and many individuals with glaucoma develop progressive loss of vision despite receiving treatment with intraocular pressure-lowering drugs. Moreover, intraocular injection is not an ideal drug delivery platform despite the overall efficacy of anti-VEGF (vascular endothelial growth factor) therapies.

  • Present research is aimed at improving our understanding of pathogenic processes, identification of potential therapeutic targets and optimization of ocular drug delivery by utilizing novel strategies such as encapsulated cell technology and applications of nanomedicine.

  • Recent scientific developments have presented new opportunities to make major advances in ophthalmology, and a vigorous effort to develop new therapies is currently underway.

Abstract

Blindness affects 60 million people worldwide. The leading causes of irreversible blindness include age-related macular degeneration, retinal vascular diseases and glaucoma. The unique features of the eye provide both benefits and challenges for drug discovery and delivery. During the past decade, the landscape for ocular drug therapy has substantially changed and our knowledge of the pathogenesis of ophthalmic diseases has grown considerably. Anti-angiogenic drugs have emerged as the most effective form of therapy for age-related macular degeneration and retinal vascular diseases. Lowering intraocular pressure is still the mainstay for glaucoma treatment but neuroprotective drugs represent a promising next-generation therapy. This Review discusses the current state of ocular drug therapy and highlights future therapeutic opportunities.

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Figure 1: Human eye structure and diseases.
Figure 2: Retinal anatomy and structure in health and diseases.
Figure 3: Proposed pathophysiology of AMD, and locations in the pathway in which different therapeutic interventions might be effective.
Figure 4: Mechanism of action of ocular angiogenesis inhibitors in clinical care or development.
Figure 5: Agents that lower intraocular pressure.
Figure 6: Complement pathways, their association with AMD and drug targets.

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Change history

  • 22 June 2012

    The second address affiliation has been updated to include the Shiley Eye Center.

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Acknowledgements

We thank J. Ambati, S. Ding, I. Kozak, J. Lee, L. Zhao and P. Shaw for their helpful comments. K.Z. is supported by grants from the Chinese National 985 Project to Sichuan University and West China Hospital, the National Eye Institute and the US National Institutes of Health, VA Merit Award, Research to Prevent Blindness, King Abdulaziz City for Science and Technology (through the University of California San Diego Center of Excellence in Nanomedicine centre grant) and the BWF (Burroughs Wellcome Fund) Clinical Scientist Award in Translational Research. L.Z. is supported by the National Science Foundation (NSF) grants CMMI1031239 and DMR1216461; R.N.W. is supported by grants from the National Eye Institute and the US National Institutes of Health (EY019692) and an unrestricted grant from Research to Prevent Blindness, New York, USA. We apologize for the omission of references owing to page limitations.

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Authors and Affiliations

  1. Department of Ophthalmology and Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China

    Kang Zhang

  2. Department of Ophthalmology, and Shiley Eye Center, University of California San Diego, La Jolla, 92093, California, USA

    Kang Zhang & Robert N. Weinreb

  3. Institute for Genomic Medicine, University of California San Diego, La Jolla, 92093, California, USA

    Kang Zhang & Liangfang Zhang

  4. Department of Nanoengineering, University of California San Diego, La Jolla, 92093, California, USA

    Liangfang Zhang

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Robert Weinreb is a consultant for Alcon, Allergan, Altheos, Amakem NV, Bausch and Lomb, Genentech, Merck, Novartis and Quark. He has received lecture honoraria or travel reimbursement from Alcon, Allergan, Bausch and Lomb, Merck and Genentech.

Kang Zhang is a consultant for Genentech, ThromboGenics and Acucela. He has received grants from the US National Institutes of Health, Genentech, the VA Merit Award and the Burroughs Wellcome Fund.

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Glossary

Age-related macular degeneration

(AMD). A disease process that is characterized by the degeneration of photoreceptor cells in the macula, leading to loss of central vision.

Diabetic retinopathy

A microvascular complication of type 2 diabetes that is characterized by increased vascular permeability in the initial stages of disease.

Glaucoma

A progressive disease that is characterized by optic disc cupping and peripheral visual field loss.

Retinal pigment epithelium

(RPE). A monolayer of pigmented cells in the retina, located between the photoreceptor cells and choroid.

Macula

A highly pigmented area near the centre of the retina that is responsible for detailed central vision.

Geographic atrophy

An advanced form of age-related macular degeneration that is characterized by the atrophy of retinal pigment epithelium and photoreceptor cells.

Choroidal neovascularization

(CNV). An advanced form of age-related macular degeneration that is characterized by the growth of abnormal blood vessels into the subretinal space.

Intraocular pressure

(IOP). The fluid pressure inside the eye, which is determined by the production and drainage of aqueous humour.

Aqueous humour

A clear, watery fluid produced by the ciliary epithelium that fills the anterior and posterior chambers of the eye.

Complement system

A part of the innate immune system that consists of approximately 25 proteins. Three pathways activate the complement system: the classical complement pathway, the alternative complement pathway and the mannose-binding pathway.

Small interfering RNA

(siRNA). Small, double-stranded RNA molecules that interfere with gene expression by binding to and promoting the degradation of mRNA.

Nanotechnology

The understanding and control of matter at dimensions between approximately 1 nm and 100 nm. It involves imaging, measuring, modelling and manipulating matter at this length scale.

Nanoparticle drugs

Nanometre-scale particles that are used to carry and transport pharmaceutical agents to improve therapeutic efficacy, drug safety and patient compliance.

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Zhang, K., Zhang, L. & Weinreb, R. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat Rev Drug Discov 11, 541–559 (2012). https://doi.org/10.1038/nrd3745

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