Breaching the retinal barrier THIS WEEK ANALYSIS

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THIS WEEK
ANALYSIS
COVER STORY
1 Breaching the retinal barrier
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9 This week in therapeutics
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INDEXES
18 Company and institution index
18 Target and compound index
Breaching the retinal
barrier
By Tim Fulmer, Senior Writer
Trinity College Dublin researchers have developed a way to use RNAi
to reversibly enhance the permeability of the blood retina barrier.1 The
technique improved systemic delivery of two small molecules to the
mouse retina, and the researchers are now adapting the approach for
use in humans.
Much like the brain, the retina has evolved cellular barriers to
exclude potentially harmful blood-borne agents while allowing passage of nutrients to ensure proper functioning. The retina has two such
barriers: the inner blood retina barrier (BRB), which consists of retinal
endothelial cells, and the outer BRB, which consists of a single layer of
retinal pigment epithelial cells.
In both retinal barriers, protein complexes called tight junctions
exist between individual cells to block passive diffusion of small molecules. Tight junctions consist of multiple types of proteins, including
the claudins.
Previous work by the Trinity group showed that RNAi knockdown
of claudin 5 (CLD5) in the mouse brain microvasculature led to a transient increase in diffusion of low–molecular weight compounds across
the blood brain barrier (BBB).2 Because of the similarities between
the brain and retina barriers, the team hypothesized that the same
approach could facilitate passage of systemically delivered therapies
into the retina.
Injection of CLD5 small interfering RNA into the mouse tail vein
led to lower levels of the protein in the retinal vasculature at 24 and
48 hours postinjection than levels in the retinal vasculature of control
mice.
These reductions correlated with opening of the BRB. A small molecule MRI contrast agent was able to cross the BRB at 24 and 48 hours
after injection of the CLD5 siRNA but not at 72 hours after injection.
In addition to transiently and reversibly opening the BRB to allow
passage of small molecules from the blood into the retina, the siRNA
did so without damaging the retina. DNA staining showed that the
increased BRB permeability did not cause neuronal cell death in any
layer of the retina.
Finally, the researchers looked at two different mouse models
of disease to evaluate the therapeutic potential of the CLD5 siRNA
approach.
In mice lacking an enzyme required to synthesize guanosine
triphosphate (GTP), a key mediator of visual phototransduction,
intraperitoneal delivery of GTP 48 hours after CLD5 siRNA injection
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This week in therapeutics (continued)
Indication
Colon cancer
Target/marker/
pathway
TRAF2 and NCK
interacting kinase
(TNIK)
Summary
Licensing status
Patent application
In vitro studies suggest that TNIK inhibitors
filed; available for
could help treat colon cancer. In mouse small
licensing
intestinal crypts and colon cancer cell lines,
TNIK was recruited to promoters of Wnt
target genes. In the colon cancer cells, small
interfering RNA knockdown of TNIK led to
lower transcription of Wnt target genes than
that seen using control siRNA, suggesting TNIK
activates Wnt signaling in colon cancer. Next
steps could include developing small molecule
TNIK inhibitors (see Wnt it rains, page 4).
Publication and contact
information
Mahmoudi, T. et al. EMBO J.;
published online Oct. 15, 2009;
doi:10.1038/emboj.2009.285
Contact: Hans Clevers,
Hubrecht Institute, Utrecht,
the Netherlands
e-mail:
h.clevers@niob.knaw.nl
SciBX 2(42); doi:10.1038/scibx.2009.1566
Published online Oct. 29, 2009
Non–small cell lung
cancer (NSCLC)
Studies in cells and in rats suggest that a class
Epidermal growth factor
receptor 1 (HER1; ERBB1); of dual HER1 and HER2 inhibitors could help
treat drug-resistant NSCLC. Synthesis and in
HER2 (ERBB2; neu)
vitro testing of 10 pyrrolidine carboxamide
analogs led to identification of 2 compounds
that inhibited the growth of HER1- or HER2expressing human cancer cell lines, including
an NSCLC cell line resistant to selective HER1
inhibitors. In rats with HER1- or HER2expressing tumors, both compounds reduced
tumor size compared with lapatinib or no
treatment. An optimized lead is in Phase I
testing to treat NSCLC.
GlaxoSmithKline plc markets the dual HER1
and HER2 inhibitor Tykerb lapatinib to treat
breast cancer. Tykerb is in Phase III testing to
treat gastric cancer and head and neck cancer,
Phase II testing to treat brain metastases of
breast cancer and Phase I/II testing to treat solid
tumors.
AstraZeneca plc’s Zactima vandetanib, an
inhibitor of HER1 and VEGF receptor 2
(KDR/FLK-1; VEGFR-2), is in registration to
treat advanced NSCLC.
Patented by
Hanmi
Pharmaceuticals
Co. Ltd.; available
for licensing or
partnering
Cha, M. et al. J. Med. Chem.;
published online Oct. 15, 2009;
doi:10.1021/jm901146p
Contact: Maeng Sup Kim,
Hanmi Research Center,
Gyeonggi-do, South Korea
e-mail:
kims@hanmi.co.kr
Contact: Seung Bum Park,
Seoul National University,
Seoul, South Korea
e-mail:
sbpark@snu.ac.kr
SciBX 2(42); doi:10.1038/scibx.2009.1567
Published online Oct. 29, 2009
Cardiovascular disease
Ischemia;
reperfusion injury
Hypoxia-inducible
factor 1A (HIF1A;
HIF1A)
Studies in mice suggest that adenoviral delivery
of HIF1A could help treat critical limb ischemia
in diabetics. In diabetic mice with ligated lateral
femoral arteries, intramuscular injection of
an adenoviral vector expressing constitutively
activated HIF1A increased recovery compared
with injection of adenoviral vector expressing
a control protein. Next steps include testing the
gene therapy in clinical trials.
SciBX 2(42); doi:10.1038/scibx.2009.1568
Published online Oct. 29, 2009
SciBX: Science–Business eXchange
Findings patented;
Sarkar, K. et al. Proc. Natl. Acad.
available for licensing Sci. USA; published online
Oct. 19, 2009;
doi:10.1073/pnas.0910561106
Contact: Gregg L. Semenza,
The Johns Hopkins University
School of Medicine,
Baltimore, Md.
e-mail:
gsemenza@jhmi.edu
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