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Keep Your Eyes Open: Challenges And Opportunities In Ophthalmic Therapeutics

Year: 2012
Type: article
Abstract: Future Medicinal ChemistryVol. 4, No. 17 Mini Focus Issue: Ophthalmology - ForewordFree AccessKeep your eyes open: challenges and opportunities in ophthalmic therapeuticsShusheng WangShusheng WangTulane University, Departments of Cell & Molecular Biology, & Ophthalmology, New Orleans, LA 70118, USA. Published Online:29 Nov 2012https://doi.org/10.4155/fmc.12.175AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: age-related macular degenerationdiabetic retinopathyglaucomaocular drug developementopthalmic therapeuticsThe eyes are our windows to the world. Major ocular diseases, including cataracts, glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), dry-eye syndrome and allergic conjunctivitis, can cause low vision and even blindness, which not only affect our daily life, but also have a significant socioeconomic and psychological impact on our society. The prevalence of vision impairment was estimated to be 147 million people worldwide in 2010 and is projected to reach 191 million in 2020 due to an increase in aging populations. The market for ophthalmic disease therapeutics is expected to reach US$18.7 billion this year and is predicted to grow steadily. Ophthalmic drug development has been in the forefront of therapeutic research partly because the eye is an accessible and immunologically isolated organ, which has the advantage of avoiding the complications of systemic drug delivery. With the recent advances in genetics, genomics and stem cell biology, the mechanisms of many ophthalmic diseases are being increasingly revealed. Accordingly, the field of ophthalmic therapeutics is facing unprecedented challenges and opportunities.Looking back in history, ophthalmic drug development has been driven by the scientific breakthroughs. For example, the discovery that VEGF is a driving force of choroidal neovascularization in AMD has led to the successful development of anti-VEGF antibodies for wet AMD therapy. The discovery that prostaglandin mediates reduction in intraocular pressure (IOP) has led to the treatment of ocular hypertension in glaucoma using prostaglandin analogues. Research over the past decade has uncovered novel mechanisms for many ocular diseases, which will likely spawn new therapeutic solutions. But this field is not without challenges: ▪ Currently there is no cure for many ocular diseases, including dry AMD, DR and glaucoma;▪ Current ophthalmic drug development is not based on the unique characteristics of ocular diseases, but mainly applies agents developed for non-ocular diseases to the eye;▪ Most of the ocular diseases are multifactorial diseases with both genetic and environmental (nutritional) risk factors, therefore many drugs only work for a subset of patients. For example, cyclosporine, acting as an immune-modulator for dry-eye disease, is only effective in approximately 15% of all patients;▪ Ophthalmic drug delivery, especially to the posterior eye, remains a considerable challenge.These challenges present unique opportunities for researchers in the field of ophthalmology to further elucidate the mechanisms of and develop innovative therapeutics and delivery approaches for ocular diseases.Despite the challenges, significant progress has recently been made toward understanding the mechanisms of several ocular diseases, which may translate into future therapeutics. Dry AMD accounts for up to 90% of the AMD cases and is currently without cure. Polymorphisms in members of the complement system, especially complement factor H (CFH), have been associated with AMD. Moreover, CFH was recently shown to protect against oxidative stress-induced inflammation in animal model. Inhibitors of the complement system and the recombinant form of CFH are being tested preclinically for AMD treatment. β-amyloid, originally implicated in Alzheimer's disease, was recently associated with pathogenesis of AMD. Anti-β-amyloid antibody has shown promise in animal models of AMD. Autophagy is currently being investigated for AMD involvement and may represent a potential therapeutics for AMD (see the perspective by Kaarniranta et al. in this issue [1]). DR is one of the leading causes of blindness in the working class. Besides laser photocoagulation and vitrectomy surgery, several therapeutic options, including protein kinase inhibitors, cyclooxygenase inhibitors, anti-VEGF compounds and slow-release steroids, are on clinical trials. Some of them may enter the market in the near future. As reviewed in this issue, pericytes and the angiopoietin-Tie-2 signaling also play an important role in the development of DR, and may be potential therapeutic targets for DR [2]. For glaucoma, the current mainstay for treatment is to lower the IOP, therefore, preventing further damage to the optic nerve. β-blocker, prostaglandin, carbonic anhydrase inhibitor, miotics, α-adrenergic agonist, or their combinations are routinely used for lowering IOP. Rho kinase inhibitors and actin depolymerization agents are currently tested in human clinical trials for safely reducing IOP. Dominant mutations in the olfactomedin (OLF) domain of myocilin have been associated with several populations of familial glaucoma, and molecular studies suggest that the OLF domain of myocilin may be a bona fide target for future glaucoma therapeutics (see editorial by Donegan and Lieberman [3]).Looking into future, the explosion in basic research in ocular biology and disease will lead to revolutionarily innovative ophthalmic therapeutics. Numerous opportunities also present themselves to researchers working on medicinal chemistry, new biomaterials and new delivery system. With the coordinated effort of all these groups, the future of ophthalmic therapeutics is bright.In this issueThis issue features a selection of mini-reviews on the current research that may lead to future ophthalmic therapeutics. Cai et al. review the role of pericyte-endothelial interaction and the angiopoietin–Tie-2 signaling in DR, as well as the potential of targeting of pericytes through–Tie-2 signaling for DR therapeutics [2]. Harkin and Chirila discusses the potential of using silk fibroin as a new biomaterial for corneal reconstruction [4]. Basavarajappa and Corson describe the role of KLF14 oncogene in the development and progression of retinoblastoma, and predict KLF14 as a potential drug target for RB [5]. Kaarniranta et al. summarize the role of autophagy in age-related macular degeneration and discuss the use of autophagy regulating kinases as potential therapeutic targets for AMD [1]. Kador discusses the unique needs and opportunities for medicinal chemists in ophthalmic therapeutics [6]. Donegan and Lieberman describe myocilin as a bona fide drug target for glaucoma, and discuss the targeting of the OLF domain of myocilin for glaucoma drug development [3]. Bengani and Chauhan [7] and Sheardown [8] discuss the challenges and prospects for drug delivery in ophthalmic therapies. There is also an interview with Chi-Chao Chan, Chief of Immunopathology Section, Laboratory of Immunology and the Head of Histology Core at the National Eye Institute at National Institutes of Health [9].We cordially invite you to enjoy the special focus issue of ophthalmic therapeutics.AcknowledgementsThe author thanks all of the contributors to this special focus issue for their outstanding contribution.Financial & competing interests disclosureS Wang was supported by a Startup fund from Tulane University, LA, USA, NIH Grant EY021862 and Research to Prevent Blindness Career Development Award. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Kaarniranta K, Kauppinen A, Blasiak J, Salminen A. Autophagy regulating kinases as potential therapeutic targets for age-related macular degeneration. Future Med. Chem.4(17),2153–2161 (2012).Link, CAS, Google Scholar2 Cai J, Ruan Q, Chen ZJ, Han S. Connection of pericyte-angiopoietin-Tie-2 system in diabetic retinopathy: friend or foe? Future Med. Chem.4(17),2163–2176 (2012).Link, CAS, Google Scholar3 Donegan RK, Lieberman RL. New direction for glaucoma therapeutics: focus on the olfactomedin domain of myocilin. Future Med. Chem.4(17),2131–2134 (2012).Link, CAS, Google Scholar4 Harkin DG, Chirila TV. Silk fibroin in ocular surface reconstruction: what is its potential as a biomaterial in ophthalmics? Future Med. Chem.4(17),2145–2147 (2012).Link, CAS, Google Scholar5 Basavarajappa HD, Corson TW. KIF14 as an oncogene in retinoblastoma: a target for novel therapeutics? Future Med. Chem.4(17),2149–2152 (2012).Link, CAS, Google Scholar6 Kador PF. Ophthalmic opportunities for the medicinal chemist. Future Med. Chem.4(17),2127–2129 (2012).Link, CAS, Google Scholar7 Bengani L, Chauhan A. Are contact lenses the solution for effective ophthalmic drug delivery? Future Med. Chem.4(17),2141–2143 (2012).Link, CAS, Google Scholar8 Sheardown H. Critical role for drug delivery in the development of new ophthalmic treatments. Future Med. Chem.4(17),2123–2125 (2012).Link, CAS, Google Scholar9 Chan C-C. Interview with Chi-Chao Chan. Future Med. Chem.4(17),2139–2140 (2012).Link, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 4, No. 17 STAY CONNECTED Metrics History Published online 29 November 2012 Published in print November 2012 Information© Future Science LtdKeywordsage-related macular degenerationdiabetic retinopathyglaucomaocular drug developementopthalmic therapeuticsAcknowledgementsThe author thanks all of the contributors to this special focus issue for their outstanding contribution.Financial & competing interests disclosureS Wang was supported by a Startup fund from Tulane University, LA, USA, NIH Grant EY021862 and Research to Prevent Blindness Career Development Award. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
DOI: 10.4155/fmc.12.175
Institution: Tulane University
Language: English
Open Access status: green
OpenAlex ID: W2038213290
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