Genetic retinal diseases such as age-related macular degeneration and monogenic diseases such as retinitis pigmentosa account for some of the commonest causes of blindness in the developed world. Diverse genetic abnormalities and environmental causes have been implicated in triggering multiple pathological mechanisms such as oxidative stress, lipofuscin deposits, neovascularisation, and programmed cell death. In recent years, inflammation has also been highlighted although whether inflammatory mediators play a central role in pathogenesis or a more minor secondary role has yet to be established. Despite this, numerous interventional studies, particularly targeting the complement system, are underway with the promise of novel therapeutic strategies for these important blinding conditions. 1. Introduction Inherited retinal diseases include some of the commonest causes of blindness in the developed world [1, 2]. Prominent examples included age-related macular degeneration (AMD), diabetic retinopathy, and the numerous monogenic conditions such as retinitis pigmentosa (RP), Stargardt’s disease, and X-linked retinoschisis. As well as causative/predisposing genetic abnormalities [3], in some cases (such as AMD), environmental factors such as smoking and diet have been highlighted [4, 5]. These aetiological factors have been associated with diverse abnormal biochemical pathways in the degenerating retina, for instance, oxidative stress [6]; lipofuscin accumulation in the retinal pigment epithelium [7]; abnormalities of the extracellular matrix [8]; mitochondrial abnormalities [9]; ischaemia with neovascularisation [10]; programmed cell death [11]. In particular in AMD and RP, inflammation has recently become a prominent member of this list of abnormal pathological pathways triggered by genetic retinal disease [12, 13]. 2. Established Links between Inflammation and Genetic Retinal Disease Early studies showed that autoantibodies can be detected in blood of AMD patients [14, 15] and that macrophages also accumulate in the choroid [16] which suggested that immune-mediated processes were involved in the pathogenesis of AMD. Renewed interest in inflammation in genetic retinal disease was, however, more recently triggered by the discovery of elements of the immune system and multiple proteins of the complement pathway within the drusen seen in AMD [17]. Although the exact pathophysiology of AMD remains largely unknown, accumulation of drusen is acknowledged as an early and major pathological hallmark of the disease, preempting damage in the retinal pigment
References
[1]
D. Pascolini and S. P. Mariotti, “Global estimates of visual impairment 2010,” British Journal of Ophthalmology, vol. 96, no. 5, pp. 614–618, 2010.
[2]
S. Resnikoff, D. Pascolini, D. Etya'ale et al., “Global data on visual impairment in the year 2002,” Bulletin of the World Health Organization, vol. 82, no. 11, pp. 844–851, 2004.
[3]
A. F. Wright, C. F. Chakarova, M. M. Abd El-Aziz, and S. S. Bhattacharya, “Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait,” Nature Reviews Genetics, vol. 11, no. 4, pp. 273–284, 2010.
[4]
S. C. Tomany, J. J. Wang, R. Van Leeuwen et al., “Risk factors for incident age-related macular degeneration: pooled findings from 3 continents,” Ophthalmology, vol. 111, no. 7, pp. 1280–1287, 2004.
[5]
J. S. L. Tan, J. J. Wang, V. Flood, E. Rochtchina, W. Smith, and P. Mitchell, “Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study,” Ophthalmology, vol. 115, no. 2, pp. 334–341, 2008.
[6]
S. M. Plafker, G. B. O'Mealey, and L. I. Szweda, “Mechanisms for countering oxidative stress and damage in retinal pigment epithelium,” International Review of Cell and Molecular Biology, vol. 298, pp. 135–177, 2012.
[7]
N. P. Boyer, D. Higbee, M. B. Currin et al., “Lipofuscin and N-retinylidene-N-retinylethanolamine (A2E) accumulate in retinal pigment epithelium in absence of light exposure: their origin is 11-cis-retinal,” Journal of Biological Chemistry, vol. 287, no. 26, pp. 22276–22286, 2012.
[8]
J. C. Booij, D. C. Baas, J. Beisekeeva, T. G. M. F. Gorgels, and A. A. B. Bergen, “The dynamic nature of Bruch's membrane,” Progress in Retinal and Eye Research, vol. 29, no. 1, pp. 1–18, 2010.
[9]
A. Swaroop, E. Y. Chew, C. B. Rickman, and G. R. Abecasis, “Unraveling a multifactorial late-onset disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration,” Annual Review of Genomics and Human Genetics, vol. 10, pp. 19–43, 2009.
[10]
L. S. Lim, P. Mitchell, J. M. Seddon, F. G. Holz, and T. Y. Wong, “Age-related macular degeneration,” The Lancet, vol. 379, no. 9827, pp. 1728–1738, 2012.
[11]
F. Doonan, G. Groeger, and T. G. Cotter, “Preventing retinal apoptosis–is there a common therapeutic theme?” Experimental Cell Research, vol. 318, no. 11, pp. 1278–1284, 2012.
[12]
K. M. Gehrs, D. H. Anderson, L. V. Johnson, and G. S. Hageman, “Age-related macular degeneration—emerging pathogenetic and therapeutic concepts,” Annals of Medicine, vol. 38, no. 7, pp. 450–471, 2006.
[13]
N. Yoshida, Y. Ikeda, S. Notomi et al., “Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa,” Ophthalmology, vol. 120, no. 1, pp. 100–105, 2013.
[14]
P. L. Penfold, J. M. Provis, J. H. Furby, P. A. Gatenby, and F. A. Billson, “Autoantibodies to retinal astrocytes associated with age-related macular degeneration,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 228, no. 3, pp. 270–274, 1990.
[15]
D. H. Gurne, M. O. M. Tso, D. P. Edward, and H. Ripps, “Antiretinal antibodies in serum of patients with age-related macular degeneration,” Ophthalmology, vol. 98, no. 5, pp. 602–607, 1991.
[16]
M. C. Killingsworth, J. P. Sarks, and S. H. Sarks, “Macrophages related to Bruch's membrane in age-related macular degeneration,” Eye, vol. 4, no. 4, pp. 613–621, 1990.
[17]
R. F. Mullins, S. R. Russell, D. H. Anderson, and G. S. Hageman, “Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease,” FASEB Journal, vol. 14, no. 7, pp. 835–846, 2000.
[18]
G. S. Hageman, P. J. Luthert, N. H. V. Chong, L. V. Johnson, D. H. Anderson, and R. F. Mullins, “An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration,” Progress in Retinal and Eye Research, vol. 20, no. 6, pp. 705–732, 2001.
[19]
S. V. Goverdhan, S. I. Khakoo, H. Gaston, X. Chen, and A. J. Lotery, “Age-related macular degeneration is associated with the genotype and the natural killer cell receptor AA haplotype,” Investigative Ophthalmology and Visual Science, vol. 49, no. 11, pp. 5077–5082, 2008.
[20]
J. W. Crabb, M. Miyagi, X. Gu et al., “Drusen proteome analysis: an approach to the etiology of age-related macular degeneration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 23, pp. 14682–14687, 2002.
[21]
I. Bhutto and G. Lutty, “Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex,” Molecular Aspects of Medicine, vol. 33, no. 4, pp. 295–317, 2012.
[22]
B. Detrick and J. J. Hooks, “Immune regulation in the retina,” Immunologic Research, vol. 47, no. 1-3, pp. 153–161, 2010.
[23]
J. R. Sparrrow, D. Hicks, and C. P. Hamel, “The retinal pigment epithelium in health and disease,” Current Molecular Medicine, vol. 10, no. 9, pp. 802–823, 2010.
[24]
R. J. Klein, C. Zeiss, E. Y. Chew et al., “Complement factor H polymorphism in age-related macular degeneration,” Science, vol. 308, no. 5720, pp. 385–389, 2005.
[25]
J. L. Haines, M. A. Hauser, S. Schmidt et al., “Complement factor H variant increases the risk of age-related macular degeneration,” Science, vol. 308, no. 5720, pp. 419–421, 2005.
[26]
A. O. Edwards, R. Ritter III, K. J. Abel, A. Manning, C. Panhuysen, and L. A. Farrer, “Complement factor H polymorphism and age-related macular degeneration,” Science, vol. 308, no. 5720, pp. 421–424, 2005.
[27]
B. Gold, J. E. Merriam, J. Zernant et al., “Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration,” Nature Genetics, vol. 38, no. 4, pp. 458–462, 2006.
[28]
A. E. Hughes, N. Orr, H. Esfandiary, M. Diaz-Torres, T. Goodship, and U. Chakravarthy, “A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration,” Nature Genetics, vol. 38, no. 10, pp. 1173–1177, 2006.
[29]
Y. Chen, M. Bedell, and K. Zhang, “Age-related macular degeneration: genetic and environmental factors of disease,” Molecular Interventions, vol. 10, no. 5, pp. 271–281, 2010.
[30]
A. M. Newman, N. B. Gallo, L. S. Hancox, et al., “Systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype-specific functional networks?” Genome Medicine, vol. 4, no. 2, p. 16, 2012.
[31]
S. L. Doyle, M. Campbell, E. Ozaki E, et al., “NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components,” Nature Medicine, vol. 18, no. 5, pp. 791–798, 2012.
[32]
V. Tarallo, Y. Hirano, B. D. Gelfand, et al., “DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88,” Cell, vol. 149, no. 4, pp. 847–859, 2012.
[33]
H. Kaneko, S. Dridi, V. Tarallo et al., “DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration,” Nature, vol. 471, no. 7338, pp. 325–332, 2011.
[34]
C. A. Dinarello, “Interleukin-1β, interleukin-18, and the interleukin-1β converting enzyme,” Annals of the New York Academy of Sciences, vol. 856, pp. 1–11, 1998.
[35]
F. Martinon, K. Burns, and J. Tschopp, “The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β,” Molecular Cell, vol. 10, no. 2, pp. 417–426, 2002.
[36]
S. Akira, S. Uematsu, and O. Takeuchi, “Pathogen recognition and innate immunity,” Cell, vol. 124, no. 4, pp. 783–801, 2006.
[37]
E. D. Boyden and W. F. Dietrich, “Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin,” Nature Genetics, vol. 38, no. 2, pp. 240–244, 2006.
[38]
Y. Zhao, J. Yang J, J. Shi, et al., “The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus,” Nature, vol. 477, no. 7366, pp. 596–600, 2011.
[39]
F. Martinon, V. Pétrilli, A. Mayor, A. Tardivel, and J. Tschopp, “Gout-associated uric acid crystals activate the NALP3 inflammasome,” Nature, vol. 440, no. 7081, pp. 237–241, 2006.
[40]
T. Fernandes-Alnemri, J. W. Yu, P. Datta, J. Wu, and E. S. Alnemri, “AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA,” Nature, vol. 458, no. 7237, pp. 509–513, 2009.
[41]
L. L. Jones and D. A. Vignali, “Molecular interactions within the IL-6/IL-12 cytokine/receptor superfamily,” Immunology Research, vol. 52, pp. 5–14, 2011.
[42]
T. Tanaka, M. Narazaki, and T. Kishimoto, “Therapeutic targeting of the interleukin-6 receptor,” Annual Reviews in Pharmacologic Toxicolgy, vol. 52, pp. 199–219, 2012.
[43]
H. Miao, Y. Tao, and X. X. Li, “Inflammatory cytokines in aqueous humor of patients with choroidal neovascularization,” Molecular Vision, vol. 18, pp. 574–580, 2012.
[44]
W. J. Fessel, “Serum protein disturbance in retinitis pigmentosa. And the association of retinitis pigmentosa with psychosis,” American Journal of Ophthalmology, vol. 53, no. 4, pp. 640–642, 1962.
[45]
A. H. Rahi, “Autoimmunity and the retina. I. Antigenic specificity of photoreceptor cells,” British Journal of Ophthalmology, vol. 54, no. 7, pp. 441–444, 1970.
[46]
A. H. Rahi, “Autoimmunity and the retina. II. Raised serum IgM levels in retinitis pigmentosa,” British Journal of Ophthalmology, vol. 57, no. 12, pp. 904–909, 1973.
[47]
D. J. Spalton, A. H. S. Rahi, and A. C. Bird, “Immunological studies in retinitis pigmentosa associated with retinal vascular leakage,” British Journal of Ophthalmology, vol. 62, no. 3, pp. 183–187, 1978.
[48]
V. G. Wong, W. R. Green, T. Kuwabara, P. R. McMaster, and T. P. Cameron, “Homologous retinal outer segment immunization in primates: a clinical and histopathological study,” Transactions of the American Ophthalmological Society, vol. 72, pp. 184–195, 1974.
[49]
C. J. J. Brinkman, A. J. L. G. Pinckers, and R. M. Broekhuyse, “Immune reactivity to different retinal antigens in patients suffering from retinitis pigmentosa,” Investigative Ophthalmology and Visual Science, vol. 19, no. 7, pp. 743–750, 1980.
[50]
C. D. Heredia, J. Huguet, N. Cols, P. Engel, and P. A. Garcia-Calderon, “Immune complexes in retinitis pigmentosa,” British Journal of Ophthalmology, vol. 68, no. 11, pp. 811–814, 1984.
[51]
B. Detrick, M. Rodrigues, C. C. Chan, M. O. Tso, and J. J. Hooks, “Expression of HLA-DR antigen on retinal pigment epithelial cells in retinitis pigmentosa,” American Journal of Ophthalmology, vol. 101, no. 5, pp. 584–590, 1986.
[52]
D. A. Newsome and R. G. Michels, “Detection of lymphocytes in the vitreous gel of patients with retinitis pigmentosa,” American Journal of Ophthalmology, vol. 105, no. 6, pp. 596–602, 1988.
[53]
N. Gupta, K. E. Brown, and A. H. Milam, “Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration,” Experimental Eye Research, vol. 76, no. 4, pp. 463–471, 2003.
[54]
H. Y. Zeng, X. A. Zhu, C. Zhang, L. P. Yang, L. M. Wu, and M. O. M. Tso, “Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice,” Investigative Ophthalmology and Visual Science, vol. 46, no. 8, pp. 2992–2999, 2005.
[55]
N. Yoshida, Y. Ikeda, S. Notomi, et al., “Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa,” Ophthalmology, vol. 120, no. 1, pp. e5–e12, 2013.
[56]
R. A. Pearson, A. C. Barber, M. Rizzi, et al., “Restoration of vision after transplantation of photoreceptors,” Nature, vol. 485, no. 7396, pp. 99–103, 2012.
[57]
A. M. Maguire, K. A. High, A. Auricchio et al., “Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial,” The Lancet, vol. 374, no. 9701, pp. 1597–1605, 2009.
[58]
A. Kusnyerik, U. Greppmaier, R. Wilke, et al., “Positioning of electronic subretinal implants in blind retinitis pigmentosa patients through multimodal assessment of retinal structures,” Investigative Ophthalmology and Visual Science, vol. 53, no. 7, pp. 3748–3755, 2012.
[59]
D. Trifunovic, A. Sahaboglu, J. Kaur, et al., “Neuroprotective strategies for the treatment of inherited photoreceptor degeneration,” Current Molecular Medicine, vol. 12, no. 5, pp. 598–612, 2012.
[60]
D. R. Lally, A. T. Gerstenblith, and C. D. Regillo, “Preferred therapies for neovascular age-related macular degeneration,” Current Opinion in Ophthalmology, vol. 23, no. 3, pp. 182–188, 2012.
[61]
E. L. Fletcher, A. I. Jobling, K. A. Vessey, C. Luu, R. H. Guymer, and P. N. Baird, “Animal models of retinal disease,” Progress in Molecular Biology and Translational Science, vol. 100, pp. 211–286, 2011.
[62]
M. E. Pennesi, M. Neuringer, and R. J. Courtney, “Animal models of age related macular degeneration,” Molecular Aspects of Medicine, vol. 33, no. 4, pp. 487–509, 2012.
[63]
A. Sallam, S. R. Taylor, and S. Lightman, “Review and update of intraocular therapy in noninfectious uveitis,” Current Opinion in Ophthalmology, vol. 22, no. 6, pp. 517–522, 2011.
[64]
Z. Yehoshua, P. J. Rosenfeld, and T. A. Albini, “Current clinical trials in dry AMD and the definition of appropriate clinical outcome measures,” Seminars in Ophthalmology, vol. 26, no. 3, pp. 167–180, 2011.
[65]
D. Ehmann and R. García, “Triple therapy for neovascular age-related macular degeneration (verteporfin photodynamic therapy, intravitreal dexamethasone, and intravitreal bevacizumab),” Canadian Journal of Ophthalmology, vol. 45, no. 1, pp. 36–40, 2010.
[66]
S. Sivaprasad, S. Patra, J. Dacosta et al., “A pilot study on the combination treatment of reduced-fluence photodynamic therapy, intravitreal ranibizumab, intravitreal dexamethasone and oral minocycline for neovascular age-related macular degeneration,” Ophthalmologica, vol. 225, no. 4, pp. 200–206, 2011.
[67]
N. J. S. London, A. Chiang, and J. A. Haller, “The dexamethasone drug delivery system: indications and evidence,” Advances in Therapy, vol. 28, no. 5, pp. 351–366, 2011.
[68]
B. Kupperman, “Safety and efficacy of dexamethasone intravitreal implant as adjunctive therapy to Lucentis in patients with choroidal neovascularization secondary to age-related macular degeneration,” in Proceedings of the 33rd Annual Macular Society Meeting, Tucson, Ariz, USA, February 2010.
[69]
F. E. Kane, J. Burdan, A. Cutino, and K. E. Green, “Iluvien: a new sustained delivery technology for posterior eye disease,” Expert Opinion on Drug Delivery, vol. 5, no. 9, pp. 1039–1046, 2008.
[70]
N. G. Kolosova, N. A. Muraleva, A. A. Zhdankina, N. A. Stefanova, A. Z. Fursova, and M. V. Blagosklonny, “Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats,” American Journal of Pathology, vol. 181, no. 2, pp. 472–477, 2012.
[71]
G. Landa, R. B. Rosen, A. Patel et al., “Qualitative spectral OCT/SLO analysis of drusen change in dry age-related macular degeneration patients treated with copaxone,” Journal of Ocular Pharmacology and Therapeutics, vol. 27, no. 1, pp. 77–82, 2011.
[72]
R. S. Kadam, P. Tyagi, H. F. Edelhauser, and U. B. Kompella, “Influence of choroidal neovascularization and biodegradable polymeric particle size on transscleral sustained delivery of triamcinolone acetonide,” International Journal of Pharmacology, vol. 434, pp. 140–147, 2012.
[73]
J. L. Olson, R. J. Courtney, and N. Mandava, “Intravitreal infliximab and choroidal neovascularization in an animal model,” Archives of Ophthalmology, vol. 125, no. 9, pp. 1221–1224, 2007.
[74]
R. Troutbeck, S. Al-Qureshi, and R. H. Guymer, “Therapeutic targeting of the complement system in age-related macular degeneration: a review,” Clinical Experimental Ophthalmology, vol. 40, no. 1, pp. 18–26, 2012.
[75]
K. Schnatbaum, E. Locardi, D. Scharn et al., “Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivo activity,” Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 19, pp. 5088–5092, 2006.
[76]
M. Fridkis-Hareli, M. Storek, I. Mazsaroff, et al., “Design and development of TT30, a novel C3d-targeted C3/C5 convertase inhibitor for treatment of human complement alternative pathway-mediated diseases,” Blood, vol. 118, no. 17, pp. 4705–4713, 2011.
[77]
B. Rohrer, Q. Long, B. Coughlin et al., “A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration,” Investigative Ophthalmology and Visual Science, vol. 50, no. 7, pp. 3056–3064, 2009.
[78]
H. Ozdemir, M. Karacorlu, and S. Karacorlu, “Intravitreal triamcinolone acetonide for treatment of cystoid macular oedema in patients with retinitis pigmentosa,” Acta Ophthalmologica Scandinavica, vol. 83, no. 2, pp. 248–251, 2005.
[79]
M. Srour, G. Querques, N. Leveziel et al., “Intravitreal dexamethasone implant (Ozurdex) for macular edema secondary to retinitis pigmentosa,” Graefe's Archive for Clinical and Experimental Ophthalmology, 2012.
[80]
R. Iezzi, B. R. Guru, I. V. Glybina, M. K. Mishra, A. Kennedy, and R. M. Kannan, “Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration,” Biomaterials, vol. 33, pp. 979–988, 2012.
[81]
M. A. Zarbin and P. J. Rosenfeld, “Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives,” Retina, vol. 30, no. 9, pp. 1350–1367, 2010.
[82]
W. Xue, R. I. Cojocaru, V. J. Dudley, M. Brooks, A. Swaroop, and V. P. Sarthy, “Ciliary neurotrophic factor induces genes associated with inflammation and gliosis in the retina: a gene profiling study of flow-sorted, müller cells,” PLoS ONE, vol. 6, no. 5, Article ID e20326, 2011.
[83]
K. Zhang, J. J. Hopkins, J. S. Heier et al., “Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 15, pp. 6241–6245, 2011.
[84]
K. E. Talcott, K. Ratnam, S. M. Sundquist et al., “Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment,” Investigative Ophthalmology and Visual Science, vol. 52, no. 5, pp. 2219–2226, 2011.
