PMID- 21552568
OWN - NLM
STAT- MEDLINE
DCOM- 20110823
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 4
DP  - 2011 Apr 28
TI  - A non membrane-targeted human soluble CD59 attenuates choroidal 
      neovascularization in a model of age related macular degeneration.
PG  - e19078
LID - 10.1371/journal.pone.0019078 [doi]
LID - e19078
AB  - Age related macular degeneration (AMD) is the most common cause of blindness 
      amongst the elderly. Approximately 10% of AMD patients suffer from an advanced 
      form of AMD characterized by choroidal neovascularization (CNV). Recent evidence 
      implicates a significant role for complement in the pathogenesis of AMD. 
      Activation of complement terminates in the incorporation of the membrane attack 
      complex (MAC) in biological membranes and subsequent cell lysis. Elevated levels 
      of MAC have been documented on choroidal blood vessels and retinal pigment 
      epithelium (RPE) of AMD patients. CD59 is a naturally occurring membrane bound 
      inhibitor of MAC formation. Previously we have shown that membrane bound human 
      CD59 delivered to the RPE cells of mice via an adenovirus vector can protect 
      those cells from human complement mediated lysis ex vivo. However, application of 
      those observations to choroidal blood vessels are limited because protection from 
      MAC- mediated lysis was restricted only to the cells originally transduced by the 
      vector. Here we demonstrate that subretinal delivery of an adenovirus vector 
      expressing a transgene for a soluble non-membrane binding form of human CD59 can 
      attenuate the formation of laser-induced choroidal neovascularization and murine 
      MAC formation in mice even when the region of vector delivery is distal to the 
      site of laser induced CNV. Furthermore, this same recombinant transgene delivered 
      to the intravitreal space of mice by an adeno-associated virus vector (AAV) can 
      also attenuate laser-induced CNV. To our knowledge, this is the first 
      demonstration of a non-membrane targeting CD59 having biological potency in any 
      animal model of disease in vivo. We propose that the above approaches warrant 
      further exploration as potential approaches for alleviating complement mediated 
      damage to ocular tissues in AMD.
FAU - Cashman, Siobhan M
AU  - Cashman SM
AD  - Department of Ophthalmology, Tufts University School of Medicine, Boston, 
      Massachusetts, United States of America.
FAU - Ramo, Kasmir
AU  - Ramo K
FAU - Kumar-Singh, Rajendra
AU  - Kumar-Singh R
LA  - eng
GR  - R01 EY014991/EY/NEI NIH HHS/United States
GR  - EY014991/EY/NEI NIH HHS/United States
GR  - EY013887/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110428
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (CD59 Antigens)
RN  - 0 (Complement Membrane Attack Complex)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Animals
MH  - CD59 Antigens/*chemistry/*genetics
MH  - Cell Line
MH  - Choroidal Neovascularization/*genetics/*therapy
MH  - Complement Membrane Attack Complex/metabolism
MH  - Dependovirus/genetics
MH  - Disease Models, Animal
MH  - Genetic Therapy/*methods
MH  - Humans
MH  - Lasers/adverse effects
MH  - Macular Degeneration/etiology/genetics/*physiopathology/*therapy
MH  - Mice
MH  - Retina/metabolism
MH  - Solubility
PMC - PMC3084256
COIS- Competing Interests: Tufts University has filed patents that include the data in 
      this manuscript. Rajendra Kumar-Singh is a consultant and equity holder in Hemera 
      Biosciences.
EDAT- 2011/05/10 06:00
MHDA- 2011/08/24 06:00
PMCR- 2011/04/28
CRDT- 2011/05/10 06:00
PHST- 2011/01/06 00:00 [received]
PHST- 2011/03/24 00:00 [accepted]
PHST- 2011/05/10 06:00 [entrez]
PHST- 2011/05/10 06:00 [pubmed]
PHST- 2011/08/24 06:00 [medline]
PHST- 2011/04/28 00:00 [pmc-release]
AID - PONE-D-11-01081 [pii]
AID - 10.1371/journal.pone.0019078 [doi]
PST - epublish
SO  - PLoS One. 2011 Apr 28;6(4):e19078. doi: 10.1371/journal.pone.0019078.