Skip to main content
SpringerLink
Log in

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

  • Conference paper
  • First Online:
Inflammation and Retinal Disease: Complement Biology and Pathology

Part of the book series: Advances in Experimental Medicine and Biology ((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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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 9:1390–1397

    Article  PubMed  CAS  Google Scholar 

  • 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 314:989–992

    Article  PubMed  CAS  Google Scholar 

  • Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308:421–424

    Article  PubMed  CAS  Google Scholar 

  • El-Mofty A, Gouras P, Eisner G, Balazs EA (1978) Macular degeneration in rhesus monkey (Macaca mulatta). Exp Eye Res 27:499–502

    Article  PubMed  CAS  Google Scholar 

  • 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 38:458–462

    Article  PubMed  CAS  Google Scholar 

  • 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):164–175

    Article  Google Scholar 

  • 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 120:139–143

    Article  PubMed  CAS  Google Scholar 

  • 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 102:7227–7232

    Article  PubMed  CAS  Google Scholar 

  • 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 308:419–421

    Article  PubMed  CAS  Google Scholar 

  • 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 74:20–39

    Article  PubMed  CAS  Google Scholar 

  • 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 49:4616–4622

    Article  PubMed  CAS  Google Scholar 

  • 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 308:385–389

    Article  PubMed  CAS  Google Scholar 

  • 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 73:540–550

    Article  PubMed  CAS  Google Scholar 

  • 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 14:835–846

    PubMed  CAS  Google Scholar 

  • 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 62:211–219

    Article  PubMed  CAS  Google Scholar 

  • 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 62:399–408

    Article  PubMed  CAS  Google Scholar 

  • 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 12:156–158

    PubMed  CAS  Google Scholar 

  • 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 129:205–214

    Article  PubMed  CAS  Google Scholar 

  • 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 72:1412–1424

    Article  PubMed  CAS  Google Scholar 

  • Stafford TJ, Anness SH, Fine BS (1984) Spontaneous degenerative maculopathy in the monkey. Ophthalmology 91:513–521

    PubMed  CAS  Google Scholar 

  • Suzuki MT, Terao K, Yoshikawa Y (2003) Familial early onset macular degeneration in cynomolgus monkeys (Macaca fascicularis). Primates 44:291–294

    Article  PubMed  Google Scholar 

  • 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 46:683–691

    Article  PubMed  Google Scholar 

  • 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 19:1683–1685

    PubMed  CAS  Google Scholar 

  • 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 314:992–993

    Article  PubMed  CAS  Google Scholar 

  • 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 357:553–561

    Article  PubMed  CAS  Google Scholar 

  • 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 13:545–548

    PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Division of Molecular & Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan

    Zai-Long Chi

Authors
  1. Zai-Long Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tsunehiko Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John D. Lambris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takeshi Iwata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zai-Long Chi .

Editor information

Editors and Affiliations

  1. Department Of Pathology Laboratory Of, Medicine, University Of Pennsylvania, Johnson Pavilion 410, Philadelphia, 19104, USA

    John D. Lambris

  2. , Department of Ophthalmology and Visual S, University of Illinois at Chicago, Chicago, 62269-3745, USA

    Anthony P. Adamis

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this paper

Cite this paper

Chi, ZL., Yoshida, T., Lambris, J.D., Iwata, T. (2010). Suppression of Drusen Formation by Compstatin, a Peptide Inhibitor of Complement C3 activation, on Cynomolgus Monkey with Early-Onset Macular Degeneration. In: Lambris, J., Adamis, A. (eds) Inflammation and Retinal Disease: Complement Biology and Pathology. Advances in Experimental Medicine and Biology, vol 703. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-5635-4_9

Download citation

Publish with us

Policies and ethics

Search

Navigation