The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 11 November 2012
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quent, and it would be difficult to imag-
ine a scenario in which the T2R genotype
would affect therapy that is usually based
on bacterial culture results. However, in
selected patient groups, such as those with
chronic sinusitis, it should be possible to
design a prospective study to determine
whether the T2R38 genotype can be used to
direct preventative antibiotic therapy.
The author’s laboratory is supported by
NIH grants RO1HL079395 and HL73989.
Address correspondence to: Alice Prince,
Department of Pediatrics, Columbia Uni-
versity, 650 West 168th Street, Black Build-
ing 418, New York, New York 10032, USA.
Phone: 212.305.4193; Fax: 212.305.2284;
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The protection mediated by T2R signaling
is likely to function against a large group
of potential Gram-negative pathogens.
AHLs are highly conserved molecules used
by many Gram-negative bacteria to coordi-
nate gene expression (8). Although P. aeru-
ginosa is the best-studied AHL system and
arguably the most relevant human patho-
gen in this group of opportunists, similar
signaling systems are widespread, particu-
larly in the marine Vibrios and Aeromonas
species, as well as in common opportunists
such as Acinetobacter and Burkholderia spe-
cies (11, 12). Thus, T2R signaling would be
expected to contribute to innate immune
defenses against a number of potential
pathogens that are associated with respi-
Given the interest in identifying genes
that confer increased risk or resistance to
specific diseases, would the identification
of a patient’s T2R38 genotype be clinically
useful? In those with known increased sus-
ceptibility to respiratory infection, such as
those with cystic fibrosis or COPD, or even
patients in intensive care units expected to
require assisted ventilation, Gram-positive
as well as Gram-negative infections are fre-
Turning a blind eye to anti-VEGF toxicities
Susan E. Quaggin
The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Division of Nephrology, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada.
Excessive blood vessel growth is a key feature of many retinal diseases, and
recently, anti-VEGF therapy has been successfully applied to treat neovascu-
lar age-related macular degeneration (AMD), diabetic macular edema, and
retinal vein occlusion. In this issue of the JCI, Kurihara et al. reveal an essen-
tial role of Vegfa in maintaining choroid vasculature and cone photorecep-
tors, critical for central and color vision. Their findings suggest that thera-
peutic approaches to blocking VEGF signaling in retinal diseases might have
unexpected detrimental side effects and that the development of alternative
strategies might be necessary.
Anti-VEGF agents are a rapidly expand-
ing group of therapeutic compounds
developed to target pathologic angiogen-
esis and excessive vascular permeability
in cancers and other diseases. They act
by blocking the action of the VEGFA
ligand or its receptors. Currently, more
than 1500 clinical trials of anti-VEGF
receptors are underway. The FDA has
already approved anti-VEGF agents for
the treatment of solid tumors, including
colon, breast, and renal cell carcinoma. A
number of eye diseases are also character-
ized by excessive blood vessel growth and
permeability, including neovascular age-
related macular degeneration (AMD),
diabetic retinopathy, and retinal vein
occlusion (1–6). In a randomized clinical
trial, patients with AMD who were treat-
ed with intravitreal injections of ranibi-
zumab (Lucentis), which inhibits VEGF
ligand binding to its receptor, exhibited
improvement in best corrected visual
acuity (BCVA) at 12 and 24 months, com-
pared with sham-injected controls (6).
These results provided the rationale
to consider using these therapies in
other retinal diseases characterized by
enhanced vascular permeability, such as
diabetic retinopathy. In an open-label
pilot study in ten patients with diabetic
macular edema (DME), multiple intravit-
real injections of ranibizumab reduced
retinal thickness and improved BCVA
at three months (7). Since this original
study, seven clinical studies demonstrat-
ing positive results for DME have been
published (3). While these results are very
encouraging and offer potential thera-
peutic value to many patients, there may
be reason for guarded optimism based
Conflict of interest: The author has declared that no
conflict of interest exists.
Citation for this article: J Clin Invest. 2012;