Phase 1 dose-escalation study of a siRNA targeting the RTP801 gene in age-related macular degeneration patients

Eye (Basingstoke)

Volumn 26, Issue 8, 2012, Pages 1099-1105

  Nguyen, Q D ^a   Schachar, R A ^b   Nduaka, C I ^b   Sperling, M ^b   Basile, A S ^b   Klamerus, K J ^b   Chi Burris, K ^b   Yan, E ^b   Paggiarino, D A ^b   Rosenblatt, I ^c   Khan, A ^d   Aitchison, R ^d   Erlich, S S ^d  

^a JOHNS HOPKINS UNIVERSITY   (United States)

^b PFIZER INC   (United States)

^c RABIN MEDICAL CENTER   (Israel)

^d QBI Enterprises Ltd   (Israel)

Author keywords

neovascular age related macular degeneration; phase 1; siRNA

Indexed keywords

PF 04523655; SMALL INTERFERING RNA; UNCLASSIFIED DRUG;

AGED; ARTICLE; BEST CORRECTED VISUAL ACUITY; BRONCHITIS; CLINICAL ARTICLE; CONJUNCTIVAL HEMORRHAGE; CONJUNCTIVAL HYPEREMIA; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG TOLERABILITY; EYE IRRITATION; EYE PAIN; FEMALE; FOREIGN BODY; HUMAN; INTRAOCULAR PRESSURE; LIMB PAIN; MALE; MULTICENTER STUDY; NAUSEA; OCULAR PRURITUS; PHASE 1 CLINICAL TRIAL; PUNCTATE KERATITIS; RETINA DETACHMENT; RETINA MACULA AGE RELATED DEGENERATION; RHINOPHARYNGITIS; SIDE EFFECT; SUBRETINAL NEOVASCULARIZATION; TREATMENT DURATION; VISUAL ACUITY; XEROSTOMIA;

EID: 84864855385     PISSN: 0950222X     EISSN: 14765454     Source Type: Journal    
DOI: 10.1038/eye.2012.106     Document Type: Article

References (16)

1. Klein R, Klein BEK, Linton KLP. Prevalence of age-related maculopathy: The Beaver Dam eye study. Ophthalmology 1992; 99: 933-943.
2. Jonasson F, Arnarsson A, Eirikadottir G, Harris TB, Launer LJ, Meuer SM et al. Prevalence of age-related macular degeneration in old persons: age, gene/environment susceptibility Reykjavik Study. Ophthalmology 2011; 118: 825-830.
3. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ, CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011; 364: 1897-1908.
4. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY et al. Ranibizumab for neovascular agerelated macular degeneration. N Engl J Med 2006; 355: 1419-1431.
5. Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006; 113: 363-372.
6. Heier JS, Boyer D, Nguyen QD, Marcus D, Roth DB, Yancopoulos G et al. The 1-year results of CLEAR-IT 2, a phase 2 study of vascular endothelial growth factor trap-eye dosed as-needed after 12-week fixed dosing. Ophthalmology 2011; 118: 1098-1106.
7. Brafman A, Mett I, Shafir M, Gottlieb H, Damari G, Gozlan-Kelner S et al. Inhibition of oxygen-induced retinopathy RTP801-deficient mice. Invest Ophthalmol Vis Sci 2004; 45: 3796-3805.
8. Rittenhouse KD, Hirakawa B, Huang W, Basile AS, Johnson TR, Schachar RA. Dose-related gene silencing of RTP801 with the siRNA PF04523655 in Long Evans rat models of STZ induced diabetes and laser induced CNV. Invest Ophthalmol Vis Sci 2010; 51, E-Abstract 6447.
9. Rittenhouse KD, Kalabat D, Yang A, Vicini P, Johnson TR, Huang W et al. Characterization of regional RTP801 gene expression within the retina and the concentration-effect relationship of PF-655, an RTP801-silencing siRNA, following intravitreous administration to diabetic rats. Invest Ophthalmol Vis Sci 2011; 52, E-Abstract 5641.
10. Shoshani T, Faerman A, Mett I, Zelin E, Tenne Y, Gorodin S et al. Identification of a novel hypoxia-inducible factor1-responsive gene, RTP801, involved in apoptosis. Mol Cell Biol 2002; 22: 2283-2293.
11. Jin H-O, An S, Lee H-C, Woo SH, Seo SK, Choe TB et al. Hypoxic condition-and high cell density-induced expression of Redd1 is regulated by activation of hypoxic-inducible factor-1a and Sp1 through the phosphatidylinositol 3 kinase/Akt signaling pathway. Cell Signal 2007; 19: 1393-1403.
12. Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K et al. REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol Cell 2002; 10: 995-1005.
13. Feinstein E, Ashush H, Kleinman ME, Nozaki M, Kalinski H, Mett I et al. PF-04523655 (REDD14), an siRNA compound targeting RTP801, penetrates retinal cells producing target gene knockdown and avoiding TLR3 activation. Invest Ophthalmol Vi Sci 2009; 50, E-Abstract 5693.
14. Kaiser PK, Symons RCA, Shah SM, Quinlan EJ, Tabandeh H, Do DV et al. RNAi-based treatment for neovascular agerelated macular degeneration by Sirna-027. Am J Opthalmol 2010; 150: 33-39.
15. Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 2009; 8: 129-138.
16. Perkel JM. RNAi therapeutics: a two-year update. Science 2009; 326: 454-456.