Toward a Higher Fidelity Model of AMD

  • Brian J. Raisler
  • Miho Nozaki
  • Judit Baffi
  • William W. Hauswirth
  • Jayakrishna Ambati
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 613)

Age-relatedmacular degeneration (AMD) is the leading cause of acquired blindness in the elderly population of industrialized countries (Klein et al., 1997; Vingerling et al., 1995; Leibowitz et al., 1980). Characterized clinically in two stages; ‘dry’ AMD consists of deposition of drusen under the RPE, particularly in the macular region, while ‘wet/exudative’ AMD consists of formation of new, invasive blood vessels originating from the choriodal vascular bed. Dry AMD can lead to vision loss due to geographic atrophy and photoreceptor loss, but most patients with drusen do not suffer loss of vision.


Choroidal Neovascularization Geographic Atrophy Gene Therapy Approach High Fidelity Model Cytoskeletal Disruption 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. AREDS Report no. 8. (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. Arch. Ophthalmol. 119, 1417–1436.Google Scholar
  2. Ambati J., Anand A., Fernandez S., Sakurai E., Lynn B.C., Kuziel W.A., Rollins B.J., & Ambati B.K. (2003) An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nat. Med. 9, 1390–1397.PubMedCrossRefGoogle Scholar
  3. Beatty S., Koh H., Phil M., Henson D., & Boulton M. (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv. Ophthalmol. 45, 115–134.PubMedCrossRefGoogle Scholar
  4. Cashman S.M., Bowman L., Christofferson J., & Kumar-Singh R. (2006) Inhibition of choroidal neovascularization by adenovirus-mediated delivery of short hairpin RNAs targeting VEGF as a potential therapy for AMD. Invest Ophthalmol. Vis. Sci. 47, 3496–3504.PubMedCrossRefGoogle Scholar
  5. Dewan A., Liu M., Hartman S., Zhang S.S., Liu D.T., Zhao C., Tam P.O., Chan W.M., Lam D.S., Snyder M., Barnstable C., Pang C.P., & Hoh J. (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314, 989–992.PubMedCrossRefGoogle Scholar
  6. Edwards A.O., Ritter R., III, Abel K.J., Manning A., Panhuysen C., & Farrer L.A. (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424.PubMedCrossRefGoogle Scholar
  7. Eter N., Krohne T.U., & Holz F.G. (2006) New pharmacologic approaches to therapy for age-related macular degeneration. BioDrugs. 20, 167–179.PubMedCrossRefGoogle Scholar
  8. Gold B., Merriam J.E., Zernant J., Hancox L.S., Taiber A.J., Gehrs K., Cramer K., Neel J., Bergeron J., Barile G.R., Smith R.T., Hageman G.S., Dean M., & Allikmets R. (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat. Genet. 38, 458–462.PubMedCrossRefGoogle Scholar
  9. Hageman G.S., Anderson D.H., Johnson L.V., Hancox L.S., Taiber A.J., Hardisty L.I., Hageman J.L., Stockman H.A., Borchardt J.D., Gehrs K.M., Smith R.J., Silvestri G., Russell S.R., Klaver C.C., Barbazetto I., Chang S., Yannuzzi L.A., Barile G.R., Merriam J.C., Smith R.T., Olsh A.K., Bergeron J., Zernant J., Merriam J.E., Gold B., Dean M., & Allikmets R. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl. Acad. Sci. U.S.A. 102, 7227–7232.PubMedCrossRefGoogle Scholar
  10. Haines J.L., Hauser M.A., Schmidt S., Scott W.K., Olson L.M., Gallins P., Spencer K.L., Kwan S.Y., Noureddine M., Gilbert J.R., Schnetz-Boutaud N., Agarwal A., Postel E.A., & Pericak-Vance M.A. (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421.PubMedCrossRefGoogle Scholar
  11. Klein R., Klein B.E., Jensen S.C., & Meuer S.M. (1997) The five-year incidence and progression of age-related maculopathy: the Beaver Dam eye study. Ophthalmology 104, 7–21.PubMedGoogle Scholar
  12. Klein R.J., Zeiss C., Chew E.Y., Tsai J.Y., Sackler R.S., Haynes C., Henning A.K., SanGiovanni J.P., Mane S.M., Mayne S.T., Bracken M.B., Ferris F.L., Ott J., Barnstable C., & Hoh J. (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389.PubMedCrossRefGoogle Scholar
  13. Leibowitz H.M., Krueger D.E., Maunder L.R., Milton R.C., Kini M.M., Kahn H.A., Nickerson R.J., Pool J., Colton T.L., Ganley J.P., Loewenstein J.I., & Dawber T.R. (1980) The Framingham eye study monograph: An ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973–1975. Surv. Ophthalmol. 24, 335–610.PubMedCrossRefGoogle Scholar
  14. Magnusson K.P., Duan S., Sigurdsson H., Petursson H., Yang Z., Zhao Y., Bernstein P.S., Ge J., Jonasson F., Stefansson E., Helgadottir G., Zabriskie N.A., Jonsson T., Bjornsson A., Thorlacius T., Jonsson P.V., Thorleifsson G., Kong A., Stefansson H., Zhang K., Stefansson K., & Gulcher J.R. (2006) CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD. PLoS. Med. 3, e5.PubMedCrossRefGoogle Scholar
  15. Mori K., Gehlbach P., Yamamoto S., Duh E., Zack D.J., Li Q., Berns K.I., Raisler B.J., Hauswirth W.W., & Campochiaro P.A. (2002) AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization. Invest Ophthalmol. Vis. Sci. 43, 1994–2000.PubMedGoogle Scholar
  16. Murata T., Cui J., Taba K.E., Oh J.Y., Spee C., Hinton D.R., & Ryan S.J. (2000) The possibility of gene therapy for the treatment of choroidal neovascularization. Ophthalmology 107, 1364–1373.PubMedCrossRefGoogle Scholar
  17. Murata T., Hangai M., Ishibashi T., Spee C., Gordon E.M., Anderson W.F., Hinton D.R., & Ryan S.J. (1998) Retrovirus-mediated gene transfer to photocoagulation-induced choroidal neovascular membranes. Invest Ophthalmol. Vis. Sci. 39, 2474–2478.PubMedGoogle Scholar
  18. Rasmussen H., Chu K.W., Campochiaro P., Gehlbach P.L., Haller J.A., Handa J.T., Nguyen Q.D., & Sung J.U. (2001) Clinical protocol. An open-label, phase I, single administration, dose-escalation study of ADGVPEDF.11D (ADPEDF) in neovascular age-related macular degeneration (AMD). Hum. Gene Ther. 12, 2029–2032.PubMedGoogle Scholar
  19. Rivera A., Fisher S.A., Fritsche L.G., Keilhauer C.N., Lichtner P., Meitinger T., & Weber B.H. (2005) Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum. Mol. Genet. 14, 3227–3236.PubMedCrossRefGoogle Scholar
  20. Saishin Y., Silva R.L., Saishin Y., Kachi S., Aslam S., Gong Y.Y., Lai H., Carrion M., Harris B., Hamilton M., Wei L., & Campochiaro P.A. (2005) Periocular gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization in a human-sized eye. Hum. Gene Ther. 16, 473–478.PubMedCrossRefGoogle Scholar
  21. Vingerling J.R., Dielemans I., Hofman A., Grobbee D.E., Hijmering M., Kramer C.F., & de Jong P.T. (1995) The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 102, 205–210.PubMedGoogle Scholar
  22. Wada M., Ogata N., Otsuji T., & Uyama M. (1999) Expression of vascular endothelial growth factor and its receptor (KDR/flk-1) mRNA in experimental choroidal neovascularization. Curr. Eye Res. 18, 203–213.PubMedCrossRefGoogle Scholar
  23. Yang Z., Camp N.J., Sun H., Tong Z., Gibbs D., Cameron D.J., Chen H., Zhao Y., Pearson E., Li X., Chien J., Dewan A., Harmon J., Bernstein P.S., Shridhar V., Zabriskie N.A., Hoh J., Howes K., & Zhang K. (2006) A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314, 992–993.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Brian J. Raisler
    • 1
  • Miho Nozaki
    • 2
  • Judit Baffi
    • 3
  • William W. Hauswirth
  • Jayakrishna Ambati
    • 4
  1. 1.Department of OphthalmologyUniversity of KentuckyLexington
  2. 2.Department of OphthalmologyUniversity of KentuckyLexington
  3. 3.Department of OphthalmologyUniversity of KentuckyLexington
  4. 4.Department of OphthalmologyUniversity of KentuckyLexington

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