Advertisement

Suppression of Drusen Formation by Compstatin, a Peptide Inhibitor of Complement C3 activation, on Cynomolgus Monkey with Early-Onset Macular Degeneration

  • Zai-Long Chi
  • Tsunehiko Yoshida
  • John D. Lambris
  • Takeshi Iwata
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 703)

Abstract

For the past 10 years, number of evidence has shown that activation of complement cascade has been associated with age-related macular degeneration (AMD). The genome wide association study in American population with dominantly dry-type AMD has revealed strong association with single nucleotide polymorphism (SNP) of complement genes. Protein composition of drusen, a deposit observed in sub-retinal space between Bruch’s membrane and retinal pigment epithelial (RPE), contains active complement molecules in human and monkey. These evidences have leaded us to consider the possibility of suppressing complement cascade in the retina to delay or reverse the onset of AMD. To test is hypothesis we used the C3 inhibitor Compstatin on primate model with early-onset macular degeneration which develop drusen in less than 2 years after birth. Our preliminary result showed drusen disappearance after 6 months of intravitreal injection.

Keywords

Retinal Pigment Epithelial Cynomolgus Monkey Polypoidal Choroidal Vasculopathy Subretinal Space Membrane Cofactor Protein 
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.

Notes

Acknowledgements

This work was supported by the research grants from the Japanese Ministry of Health, Labour and Welfare (TI) and NIH grants GM-62134, and AI-068730 (JDL). The authors thank Cedric Francois and Paul Olson of Potentia Pharmaceuticals Inc., for providing us the GM grade compstatin.

References

  1. Ambati J, Anand A, Fernandez S, Sakurai E, Lynn BC, Kuziel WA, Rollins BJ, Ambati BK (2003) An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nat Med 9:1390–1397PubMedCrossRefGoogle Scholar
  2. Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, Tam PO, Chan WM, Lam DS, Snyder M, Barnstable C, Pang CP, Hoh J (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314:989–992PubMedCrossRefGoogle Scholar
  3. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308:421–424PubMedCrossRefGoogle Scholar
  4. El-Mofty A, Gouras P, Eisner G, Balazs EA (1978) Macular degeneration in rhesus monkey (Macaca mulatta). Exp Eye Res 27:499–502PubMedCrossRefGoogle Scholar
  5. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT, AMD Genetics Clinical Study Group, Hageman GS, 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 38:458–462PubMedCrossRefGoogle Scholar
  6. Goto A, Akahori M, Okamoto H, Minami M, Terauchi N, Haruhata Y, Obazawa M, Noda T, Honda M, Mizota A, Tanaka M, Hayashi T, Tanito M, Ogata N, Iwata T (2009) Genetic analysis of typical wet-type age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese population. J Biochem Dis Inform 2(4):164–175CrossRefGoogle Scholar
  7. Gotoh N, Yamada R, Hiratani H, Renault V, Kuroiwa S, Monet M, Toyoda S, Chida S, Mandai M, Otani A, Yoshimura N, Matsuda F (2006) No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese. Hum Genet 120:139–143PubMedCrossRefGoogle Scholar
  8. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, 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 USA 102:7227–7232PubMedCrossRefGoogle Scholar
  9. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308:419–421PubMedCrossRefGoogle Scholar
  10. Iyengar SK, Song D, Klein BE, Klein R, Schick JH, Humphrey J, Millard C, Liptak R, Russo K, Jun G, Lee KE, Fijal B, Elston RC (2004) Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. Am J Hum Genet 74:20–39PubMedCrossRefGoogle Scholar
  11. Katragadda M, Magotti P, Sfyroera G, Lambris JD (2006) Hydrophobic effect and hydrogen bonds account for the improved activity of a complement inhibitor, compstatin. J Med Chem 49:4616–4622PubMedCrossRefGoogle Scholar
  12. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308:385–389PubMedCrossRefGoogle Scholar
  13. Majewski J, Schultz DW, Weleber RG, Schain MB, Edwards AO, Matise TC, Acott TS, Ott J, Klein ML (2003) Age-related macular degeneration – a genome scan in extended families. Am J Hum Genet 73:540–550PubMedCrossRefGoogle Scholar
  14. Mullins RF, Russell SR, Anderson DH, Hageman GS (2000) 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 J 14:835–846PubMedGoogle Scholar
  15. Nicolas MG, Fujiki K, Murayama K, Suzuki MT, Mineki R, Hayakawa M, Yoshikawa Y, Cho F, Kanai A (1996a) Studies on the mechanism of early onset macular degeneration in cynomolgus (Macaca fascicularis) monkeys. I. Abnormal concentrations of two proteins in the retina. Exp Eye Res 62:211–219PubMedCrossRefGoogle Scholar
  16. Nicolas MG, Fujiki K, Murayama K, Suzuki MT, Shindo N, Hotta Y, Iwata F, Fujimura T, Yoshikawa Y, Cho F, Kanai A (1996b) Studies on the mechanism of early onset macular degeneration in cynomolgus monkeys. II. Suppression of metallothionein synthesis in the retina in oxidative stress. Exp Eye Res 62:399–408PubMedCrossRefGoogle Scholar
  17. Okamoto H, Umeda S, Obazawa M, Minami M, Noda T, Mizota A, Honda M, Tanaka M, Koyama R, Takagi I, Sakamoto Y, Saito Y, Miyake Y, Iwata T (2006) Complement factor H polymorphisms in Japanese population with age-related macular degeneration. Mol Vis 12:156–158PubMedGoogle Scholar
  18. Russell SR, Mullins RF, Schneider BL, Hageman GS (2000) Location, substructure, and composition of basal laminar drusen compared with drusen associated with aging and age-related macular degeneration. Am J Ophthalmol 129:205–214PubMedCrossRefGoogle Scholar
  19. Schick JH, Iyengar SK, Klein BE, Klein R, Reading K, Liptak R, Millard C, Lee KE, Tomany SC, Moore EL, Fijal BA, Elston RC (2003) A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study. Am J Hum Genet 72:1412–1424PubMedCrossRefGoogle Scholar
  20. Stafford TJ, Anness SH, Fine BS (1984) Spontaneous degenerative maculopathy in the monkey. Ophthalmology 91:513–521PubMedGoogle Scholar
  21. Suzuki MT, Terao K, Yoshikawa Y (2003) Familial early onset macular degeneration in cynomolgus monkeys (Macaca fascicularis). Primates 44:291–294PubMedCrossRefGoogle Scholar
  22. Umeda S, Ayyagari R, Allikmets R, Suzuki MT, Karoukis AJ, Ambasudhan R, Zernant J, Okamoto H, Ono F, Terao K, Mizota A, Yoshikawa Y, Tanaka Y, Iwata T (2005a) Early-onset macular degeneration with drusen in a cynomolgus monkey (Macaca fascicularis) pedigree: exclusion of 13 candidate genes and loci. Invest Ophthalmol Vis Sci 46:683–691PubMedCrossRefGoogle Scholar
  23. Umeda S, Suzuki MT, Okamoto H, Ono F, Mizota A, Terao K, Yoshikawa Y, Tanaka Y, Iwata T (2005b) Molecular composition of drusen and possible involvement of anti-retinal autoimmunity in two different forms of macular degeneration in cynomolgus monkey (Macaca fascicularis). FASEB J 19:1683–1685PubMedGoogle Scholar
  24. Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K (2006) A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314:992–993PubMedCrossRefGoogle Scholar
  25. Yates JRW, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT (2007) Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 357:553–561PubMedCrossRefGoogle Scholar
  26. Yoshida T, Wan AD, Zhang H, Sakamoto R, Okamoto H, Minami M, Obazawa M, Mizota A, Tanaka M, Saito Y, Takagi I, Hoh J, Iwata T (2007) HTRA1 promoter polymorphism predisposes Japanese to AMD. Mol Vis 13:545–548PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Zai-Long Chi
    • 1
  • Tsunehiko Yoshida
  • John D. Lambris
  • Takeshi Iwata
  1. 1.Division of Molecular & Cellular BiologyNational Institute of Sensory Organs, National Hospital Organization Tokyo Medical CenterTokyoJapan

Personalised recommendations