&2/-4(%-!+%23/&!.$ /#4/"%2s6/,5-%.5-"%2 THIS WEEK ANALYSIS COVER STORY 1 Breaching the retinal barrier 4RINITY#OLLEGE$UBLINRESEARCHERSHAVEDEMONSTRATEDTHAT 2.!ICANBEUSEDTOREVERSIBLYINCREASETHEPERMEABILITY OFTHEBLOODRETINABARRIERANDDELIVERSMALLMOLECULESTO THEMOUSERETINA4HERESEARCHERSARENOWADAPTINGTHE APPROACHFORUSEINHUMANS TARGETS & MECHANISMS 4 Wnt it rains UTCHRESEARCHERSHAVEFOUNDANEWTARGETINTHE7NT $ PATHWAYCALLED4.)+4HEKINASECOULDBEDRUGGABLEAND MAYBEAGOODTARGETINCOLONANDOTHERCANCERS"UT 4.)+SGENERALEXPRESSIONPATTERNWILLHAVETOBEANALYZED TOEVALUATETHEPOTENTIALSIDEEFFECTSOFINHIBITINGIT 5 New autoimmunity targets EWLYPUBLISHEDRESEARCHSUGGESTSTHATANTAGONIZINGTHE . SOLUBLEFORMOF&!3,ORAGONIZING00!2DCOULDBOOSTTHE KILLINGANDCLEARANCEOFAPOPTOTICCELLSTHESOURCEOFMANY SELFANTIGENSANDTHUSHELPTREATAUTOIMMUNECONDITIONS 4HECHALLENGEISTOSUBTLYMANIPULATETHESETARGETSWITHOUT ELICITINGUNWANTEDSIDEEFFECTS TOOLS 7 More iPS cells in less time CRIPPSRESEARCHERSHAVEDEVELOPEDASMALLMOLECULE 3 APPROACHTHATPROVIDESMORETHANAFOLDBOOSTINTHE GENERATIONOFINDUCEDPLURIPOTENTSTEMCELLSFROMHUMAN lBROBLASTSWHILECUTTINGTHEGENERATIONTIMEINHALF&ATE 4HERAPEUTICSHOPESTOAPPLYTHETECHNOLOGYTOITSPLATFORM FORPRODUCINGPHARMACEUTICALGRADEI03CELLSFORDRUG DISCOVERYANDTHERAPEUTICUSE THE DISTILLERY 9 This week in therapeutics REDICTINGSUSCEPTIBILITYTOSEVENAUTOIMMUNEDISORDERS 0 THROUGHHLA3.0ANALYSISINCREASINGTHEEFlCACYOF PACLITAXELWITH-03ANTAGONISTSUSING 4206INHIBITORS TOTREATPAINTREATINGOCULARHYPERTENSIONWITH,)-+ INHIBITORSANDMOREx 17 This week in techniques 03!ASSAYFOREARLYDETECTIONOFPROSTATECANCER ! RECURRENCEAMOUSEMODELOFSUDDENUNEXPLAINEDDEATHIN EPILEPSY MOLECULARMARKERSOFTRULYPLURIPOTENTHUMANI03 CELLS ANDMOREx 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 1 4(%$)34),,%29 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: [email protected] 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: [email protected] Contact: Seung Bum Park, Seoul National University, Seoul, South Korea e-mail: [email protected] 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: [email protected] /#4/"%2s6/,5-%.5-"%2 12