Granted Patent
B2
US 12,636,348 · App. 17/328,705 · Granted May 26, 2026
Treatment of ocular neovascularization using anti-vegf proteins
Inventors:
Ian J. Constable (Mosman Park, AU); P. Elizabeth Rakoczy (Scarborough, AU); Chooi-May Lai (Waterford, AU); Thomas W. Chalberg, Jr. (Redwood City, CA)
Assignee:
Avalanche Australia Pty Ltd
A61K38/45A61B3/032A61K31/7088A61K35/761A61K38/179A61K45/06A61K48/00A61K48/0075A61K49/0004C07K14/71C07K16/081C07K16/22C12N7/00C12N9/12C12N15/86C12Y207/10001C12Y207/10002A61K9/0048A61K2039/505C07K2317/24C07K2317/55C07K2317/73C07K2319/32C12N2710/14044C12N2750/14141C12N2750/14142C12N2750/14143C12N2750/14171C12Y207/10
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The present disclosure provides compositions and methods for the prevention or treatment of ocular neovascularization, such as AMD, in a human subject, by administering subretinally a pharmaceutical composition comprising a pharmaceutically effective amount of a vector comprising a nucleic acid encoding soluble Fms-related tyrosine kinase-1 (sFlt-1) protein to the human subject.
Claims (27)
1 . A method for the treatment of ocular neovascularization in a human subject suffering from ocular neovascularization, the method comprising:
i) administering a first dose of an anti-Vascular Endothelial Growth Factor (anti-VEGF) agent to the human subject;
ii) within 90 days of administering the anti-VEGF agent to the eye according to step (i), administering to the eye of the human subject a single unit dose of a pharmaceutical composition comprising a recombinant adeno-associated virus (rAAV) comprising a nucleic acid sequence encoding an anti-VEGF protein, wherein the anti-VEGF protein comprises a polypeptide selected from the group consisting of (a) a polypeptide having at least 90% identity to SEQ ID NO: 121 and (b) a polypeptide having at least 90% identity to SEQ ID NO: 121 plus a domain 3, wherein the domain 3 is selected from domain 3 of sFLT and domain 3 of KDR, wherein the single unit dose comprises at least 1×10 6 and at most 1×10 15 vector genomes of the rAAV; and
iii) administering a second dose of an anti-VEGF agent within 30 days post administration of the rAAV.
2 . The method of claim 1 , wherein the human subject has or is suspected of having one or more conditions selected from the group consisting of: age-related macular degeneration (AMD), wet-AMD, dry-AMD, retinal neovascularization, choroidal neovascularization and diabetic retinopathy.
3 . The method of claim 1 , wherein the human subject has or is suspected of having one or more conditions selected from the group consisting of: proliferative diabetic retinopathy, retinal vein occlusion, central retinal vein occlusion, branched retinal vein occlusion, diabetic macular edema, diabetic retinal ischemia, ischemic retinopathy and diabetic retinal edema.
4 . The method of claim 1 , wherein the rAAV is selected from AAV2 and AAV8.
5 . The method of claim 4 , wherein no increased anti-AAV cytotoxic T cell response is measured following the administering step.
6 . The method of claim 4 , wherein no virus is detected in the human subject's blood, saliva or urine samples, 3, 7, 14, 21 or 30 days after administering the pharmaceutical composition.
7 . The method of claim 1 , wherein the anti-VEGF protein consists of a polypeptide having at least 95% identity to SEQ ID NO: 121.
8 . The method of claim 1 , wherein the anti-VEGF protein consists of a polypeptide having at least 90% identity to SEQ ID NO:121 and a domain 3, wherein said domain 3 is selected from domain 3 of sFLT and domain 3 of KDR.
9 . The method of claim 1 , wherein the single unit dose comprises at least 1×10 9 and at most 3×10 13 vector genomes of the rAAV.
10 . The method of claim 9 , wherein the eye of the subject receives the first dose of the anti-VEGF agent in i) between about 1 to 30 days prior to the administration of the pharmaceutical composition.
11 . The method of claim 10 , wherein the anti-VEGF agent is aflibercept or ranibizumab.
12 . The method of claim 1 , wherein the administering is performed outside the fovea.
13 . The method of claim 1 , wherein a best corrected visual acuity (BCVA) of the human subject improves by at least 1, 2, 3, 4 or 5 lines as measured by ETD RS (Early Treatment Diabetic Retinopathy Study) letters following the administering of the pharmaceutical composition.
14 . The method of claim 1 , wherein a best corrected visual acuity (BCVA) of the human subject decreases by fewer than 15 letters as measured by ETDRS (Early Treatment Diabetic Retinopathy Study) following the administering of the pharmaceutical composition.
15 . The method of claim 1 , wherein administering the pharmaceutical composition is performed under conditions selected from the group consisting of: administering the pharmaceutical composition in one eye, administering the pharmaceutical composition sequentially in two eyes, and administering the pharmaceutical composition simultaneously in two eyes.
16 . The method of claim 1 , wherein a reduction in neovascularization, as observed by a Fluorescein Angiography (FA), follows the administering of the pharmaceutical composition.
17 . The method of claim 1 , wherein no superficial, anterior segment or vitreous inflammatory signs are present in the human subject at least 1 week after administration of the single unit dose of ii.
18 . The method of claim 1 , wherein the human subject has sensitivity or allergy to penicillin.
19 . The method of claim 1 , wherein the administration of the single unit dose of ii) does not increase systemic levels of sFlt-1 in the human subject.
20 . The method of claim 1 , wherein the administering of the pharmaceutical composition is performed at a frequency less than 3 times a year in the human subject.
21 . The method of claim 1 , wherein the administering of the pharmaceutical composition reduces the frequency of administration of additional VEGF inhibitor treatments in the human subject.
22 . The method of claim 1 , wherein the method comprises administering to the eye of the human subject the single unit dose of the pharmaceutical composition within 60 days of administering the anti-VEGF agent to the eye according to step (i).
23 . The method of claim 22 , wherein the method comprises administering to the eye of the human subject the single unit dose of the pharmaceutical composition within 30 days of administering the anti-VEGF agent to the eye according to step (i).
24 . A unit dose of a pharmaceutical composition for use in a method for the treatment of an ocular neovascular disease in a human subject having ocular neovascularization, the unit dose comprising recombinant adeno-associated viruses (rAAVs) of 1×1010 to 3×1012 vector genomes of the rAAV, wherein the recombinant viruses comprise a promoter operatively linked to a nucleic acid sequence encoding an anti-VEGF protein, wherein the anti-VEGF protein comprises a polypeptide selected from the group consisting of (a) a polypeptide having at least 90% identity to SEQ ID NO: 121 and (b) a polypeptide having at least 90% identity to SEO ID NO: 121 plus a domain 3, wherein domain 3 is selected from domain 3 of sFLT and domain 3 of KDR, wherein the human subject has previously received a first intravitreal injection of an anti-Vascular Endothelial Growth Factor (VEGF) agent in an amount such that the anti-VEGF agent is present in the eye of the subject at a concentration sufficient to prevent progression of the neovascularization at the time of administration of the unit dose.
Assignments (4)
SECURITY INTEREST
Recorded Oct 24, 2025
From: ADVERUM BIOTECHNOLOGIES, INC.; AVALANCHE AUSTRALIA PTY LTD
To: ELI LILLY AND COMPANY
Reel/Frame 072667/0827 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Dec 5, 2022
From: CONSTABLE, IAN J.; RAKOCZY, P. ELIZABETH; LAI, CHOOI-MAY
To: LIONS EYE INSTITUTE LIMITED
Reel/Frame 061979/0257 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Dec 5, 2022
From: CHALBERG, THOMAS W., JR.
To: AVALANCHE AUSTRALIA PTY LTD.
Reel/Frame 061979/0376 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Dec 5, 2022
From: LIONS EYE INSTITUTE LIMITED
To: AVALANCHE AUSTRALIA PTY LTD.
Reel/Frame 061979/0448 →
Continuity (10)
Provisional Application
61775440
· Mar 8, 2013
Provisional Application
61691660
· Aug 21, 2012
Provisional Application
61678555
· Aug 1, 2012
Provisional Application
61670535
· Jul 11, 2012
Provisional Application
61647461
· May 15, 2012
References Cited (400)
US 4522811A
· Eppstein et al.
· 1985
[cited by applicant]
US 4874237A
· Cringle
· 1989
[cited by applicant]
US 5219401A
· Cathignol et al.
· 1993
[cited by applicant]
US 5383917A
· Desai et al.
· 1995
[cited by applicant]
US 5436146A
· Shenk et al.
· 1995
[cited by applicant]
US 5527533A
· Tso et al.
· 1996
[cited by applicant]
US 5641749A
· Yan et al.
· 1997
[cited by applicant]
US 5712380A
· Kendall et al.
· 1998
[cited by applicant]
US 5753500A
· Shenk et al.
· 1998
[cited by applicant]
US 5792845A
· O'Reilly et al.
· 1998
[cited by applicant]
US 5814618A
· Bujard et al.
· 1998
[cited by applicant]
US 5861484A
· Kendall et al.
· 1999
[cited by applicant]
US 5994136A
· Naldini et al.
· 1999
[cited by applicant]
US 6013516A
· Verma et al.
· 2000
[cited by applicant]
US 6040183A
· Ferrari et al.
· 2000
[cited by applicant]
US 6054485A
· Schwartz et al.
· 2000
[cited by applicant]
US 6093570A
· Ferrari et al.
· 2000
[cited by applicant]
US 6132732A
· Young et al.
· 2000
[cited by applicant]
US 6153436A
· Hermonat et al.
· 2000
[cited by applicant]
US 6287815B1
· Brown
· 2001
[cited by applicant]
US 6329181B1
· Xiao et al.
· 2001
[cited by applicant]
US 6387670B1
· Leblois-Prehaud et al.
· 2002
[cited by applicant]
US 6458157B1
· Suaning
· 2002
[cited by applicant]
US 6482634B1
· Wilson et al.
· 2002
[cited by applicant]
US 6548286B1
· Samulski et al.
· 2003
[cited by applicant]
US 6723551B2
· Kotin et al.
· 2004
[cited by applicant]
US 6943153B1
· Manning, Jr. et al.
· 2005
[cited by applicant]
US 7070959B1
· Papadopoulos et al.
· 2006
[cited by applicant]
US 7071159B2
· Kendall et al.
· 2006
[cited by applicant]
US 7186699B2
· Harding et al.
· 2007
[cited by applicant]
US 7220577B2
· Zolotukhin
· 2007
[cited by applicant]
US 7585676B2
· Mitrophanous et al.
· 2009
[cited by applicant]
US 7635474B2
· Daly et al.
· 2009
[cited by applicant]
US 7666405B2
· Amalfitano et al.
· 2010
[cited by applicant]
US 7858367B2
· Amalfitano et al.
· 2010
[cited by applicant]
US 7972278B2
· Graham et al.
· 2011
[cited by applicant]
US 8075137B2
· Klistorner et al.
· 2011
[cited by applicant]
US 8118752B2
· Hetling et al.
· 2012
[cited by applicant]
US 8137274B2
· Weng et al.
· 2012
[cited by applicant]
US 8163543B2
· Urabe et al.
· 2012
[cited by applicant]
US 8343067B2
· Jones et al.
· 2013
[cited by applicant]
US 8663624B2
· Schaffer et al.
· 2014
[cited by applicant]
US 8900858B2
· Trono et al.
· 2014
[cited by applicant]
US 9193956B2
· Schaffer et al.
· 2015
[cited by applicant]
US 9198595B2
· Neitz et al.
· 2015
[cited by applicant]
US 9233131B2
· Schaffer et al.
· 2016
[cited by applicant]
US 9441244B2
· Schaffer et al.
· 2016
[cited by applicant]
US 9457103B2
· Schaffer et al.
· 2016
[cited by applicant]
US 9458517B2
· Schaffer et al.
· 2016
[cited by applicant]
US 9943573B2
· Constable et al.
· 2018
[cited by applicant]
US 20020168342A1
· Wang et al.
· 2002
[cited by applicant]
US 20020194630A1
· Manning, Jr. et al.
· 2002
[cited by applicant]
US 20040102765A1
· Koenig
· 2004
[cited by applicant]
US 20040234505A1
· Naylor et al.
· 2004
[cited by applicant]
US 20060166363A1
· Zolotukhin et al.
· 2006
[cited by applicant]
US 20060193830A1
· Hauswirth et al.
· 2006
[cited by applicant]
US 20060234347A1
· Harding et al.
· 2006
[cited by applicant]
US 20070190028A1
· Qu et al.
· 2007
[cited by applicant]
US 20070190058A1
· Shams
· 2007
[cited by applicant]
US 20080070855A1
· Gills
· 2008
[cited by applicant]
US 20080152654A1
· Reich
· 2008
[cited by applicant]
US 20090098139A1
· Katz et al.
· 2009
[cited by applicant]
US 20090191597A1
· Samulski et al.
· 2009
[cited by applicant]
US 20090285826A1
· Bonnel et al.
· 2009
[cited by applicant]
US 20100008170A1
· Sato et al.
· 2010
[cited by applicant]
US 20100081707A1
· Ali et al.
· 2010
[cited by applicant]
US 20110052678A1
· Shantha et al.
· 2011
[cited by applicant]
US 20110270256A1
· Nelson et al.
· 2011
[cited by applicant]
US 20120172419A1
· Neitz et al.
· 2012
[cited by applicant]
US 20120225930A1
· Acland et al.
· 2012
[cited by applicant]
US 20130323302A1
· Constable et al.
· 2013
[cited by applicant]
US 20140341977A1
· Constable et al.
· 2014
[cited by applicant]
US 20140364338A1
· Schaffer et al.
· 2014
[cited by applicant]
US 20140371438A1
· Constable et al.
· 2014
[cited by applicant]
US 20150025939A1
· Chatterjee et al.
· 2015
[cited by applicant]
US 20150111275A1
· Palanker et al.
· 2015
[cited by applicant]
US 20160015288A1
· Neitz et al.
· 2016
[cited by applicant]
US 20180311319A1
· Constable et al.
· 2018
[cited by applicant]
US 20190142975A1
· Keravala et al.
· 2019
[cited by applicant]
US 20190154667A1
· Keravala et al.
· 2019
[cited by applicant]
US 20210130413A1
· Keravala
· 2021
[cited by applicant]
EP 0407122A1
· 1991
[cited by applicant]
EP 2292781A1
· 2011
[cited by applicant]
EP 2298925A2
· 2011
[cited by applicant]
EP 2849802
· 2015
[cited by applicant]
JP H11100327A
· 1999
[cited by applicant]
JP 2002539176A
· 2002
[cited by applicant]
JP 2002363107A
· 2002
[cited by applicant]
JP 6466322B2
· 2019
[cited by applicant]
WO WO9208796A1
· 1992
[cited by applicant]
WO WO9428143A1
· 1994
[cited by applicant]
WO WO9522618A1
· 1995
[cited by applicant]
WO WO9526409A1
· 1995
[cited by applicant]
WO WO9813071A1
· 1998
[cited by applicant]
WO WO9851323A1
· 1998
[cited by applicant]
WO WO9914354A1
· 1999
[cited by applicant]
WO WO9916889A1
· 1999
[cited by applicant]
WO WO9936511A2
· 1999
[cited by applicant]
WO WO9945952A2
· 1999
[cited by applicant]
WO WO9966959A2
· 1999
[cited by applicant]
WO WO2000001815A2
· 2000
[cited by applicant]
WO WO2000015822A1
· 2000
[cited by applicant]
WO WO200212525A2
· 2002
[cited by applicant]
WO WO2002082904A2
· 2002
[cited by applicant]
WO WO2003080648A2
· 2003
[cited by applicant]
WO WO2004079332A2
· 2004
[cited by applicant]
WO WO2005005610A2
· 2005
[cited by applicant]
WO 2006031689A2
· 2006
[cited by applicant]
WO WO2006110689A2
· 2006
[cited by applicant]
WO WO2007084773A2
· 2007
[cited by applicant]
WO WO2007148971A2
· 2007
[cited by applicant]
WO WO2008142124A1
· 2008
[cited by applicant]
WO WO2008150459A1
· 2008
[cited by applicant]
WO WO2009073551A2
· 2009
[cited by applicant]
WO WO2009104964A1
· 2009
[cited by applicant]
WO WO2009105669A2
· 2009
[cited by applicant]
WO WO2010099960A2
· 2010
[cited by applicant]
WO WO2011020710A2
· 2011
[cited by applicant]
WO WO2011034947A2
· 2011
[cited by applicant]
WO WO2011088081A1
· 2011
[cited by applicant]
WO WO2011112089A2
· 2011
[cited by applicant]
WO WO2011122950A1
· 2011
[cited by applicant]
WO WO2011126808A2
· 2011
[cited by applicant]
WO WO2011137344A2
· 2011
[cited by applicant]
WO WO2012068317A2
· 2012
[cited by applicant]
WO WO2012145601A2
· 2012
[cited by applicant]
WO WO2013173129A2
· 2013
[cited by applicant]
WO WO2013188316A1
· 2013
[cited by applicant]
WO WO2014186160A1
· 2014
[cited by applicant]
WO WO2014207190A1
· 2014
[cited by applicant]
WO WO2015048534A1
· 2015
[cited by applicant]
WO WO2015134643A1
· 2015
[cited by applicant]
WO WO2015142941A1
· 2015
[cited by applicant]
WO WO2016141078A1
· 2016
[cited by applicant]
WO WO2017112868A1
· 2017
[cited by applicant]
WO WO2017190125A1
· 2017
[cited by applicant]
WO WO2018075798A1
· 2018
[cited by applicant]
WO WO2018160686A1
· 2018
[cited by applicant]
WO WO2018170473A1
· 2018
[cited by applicant]
Batt et al. Prophylactic Antibiotic Use After Intravitreal Injection: Effect on Endophthalmitis Rate. Retina, 2011. 31(10) 2032-2036 ( Author Manuscript, 9 pages).
[cited by examiner]
Acland, et al., “Long-term restoration of rod and cone vision by single dose rAAV mediated gene transfer to the retina in a canine model of childhood blindness.” Mol Ther. 2005; 12(6): 1072-1082.
[cited by applicant]
Adamis, et al., “Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate.” Arch Ophthalmol. 1996; 114(1): 66-71.
[cited by applicant]
Adhi, et al., “Optical coherence tomography current and future applications.” Curr Opin Ophthalmol. 2013; 24(3): 213-221.
[cited by applicant]
Aflibercept FDA Entry and Label, 2015. 28 pages. downloaded fromhttp://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label-_ApprovalHistory#apphist.
[cited by applicant]
Aiello, et al., “Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins.” Proc Natl Acad Sci USA. 1995; 92(23):10457-10…
[cited by applicant]
Akimoto, et al., “Adenovirally expressed basic fibroblast growth factor rescues photoreceptor cells in RCS rats.” Invest Ophthalmol Vis Sci. 1999; 40(2): 273-279.
[cited by applicant]
Albert, Henrik, et al. “Site specific integration of DNA into wildtype and mutant lox sites placed in the plant genome.” The Plant Journal (1995); 7.4: 649-659.
[cited by applicant]
Alexander, John J., et al. “Restoration of cone vision in a mouse model of achromatopsia.” Nature Medicine (2007); 13.6: 685-687.
[cited by applicant]
Ali, et al., “Gene therapy for inherited retinal degeneration.” Br J Ophthalmol. 1997; 81(9): 795-801.
[cited by applicant]
Amado, et al., “Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness.” Sci Transl Med. 2010; 2(21): 21ra16. doi: 10.1126/scitranslmed.3000659.
[cited by applicant]
Anand, et al., “A deviant immune response to viral proteins and transgene product is generated on subretinal administration of adenovirus and Adeno-associated virus.” Mol Ther. 2002; 5(2):125-132.
[cited by applicant]
Arnold, et al., “Extracts from “clinical evidence”: age related macular degeneration.” BMJ. 2000; 321(7263):741-744.
[cited by applicant]
Auricchio, et al., “Exchange of surface proteins impacts on viral vector cellular specificity and transduction characteristics: the retina as a model.” Hum Mol Genet. 2001; 10(26): 3075-3081.
[cited by applicant]
Auricchio, et al., “Inhibition of retinal neovascularization by intraocular viral-mediated delivery of anti-angiogenic agents.” Mol Ther. 2002; 6(4): 490-494.
[cited by applicant]
[Author Unknown] Aflibercept, Drugs RD (2008); 9(4): 261-269.
[cited by applicant]
Bailey, et al., “Exercise increases soluble vascular endothelial growth factor receptor-1 (sFlt-1) in circulation of healthy volunteers.” Med Sci Monit. 2006; 12(2): CR45-50.
[cited by applicant]
Bainbridge, et al., “Effect of gene therapy on visual function in Leber's congenital amaurosis.” N Engl J Med. 2008; 358(21): 2231-2239.
[cited by applicant]
Bainbridge, et al., “Inhibition of retinal neovascularisation by gene transfer of soluble VEGF receptor sFlt-1.” Gene Ther. 2002; 9(5): 320-326.
[cited by applicant]
Bainbridge, J. W., and Ali, R. R. “The eyes have it! Ocular gene therapy trials for LCA look promising.” Gene Ther (2008); 15: 1191-1192.
[cited by applicant]
Barleon, et al., “Mapping of the sites for ligand binding and receptor dimerization at the extracellular domain of the vascular endothelial growth factor receptor FLT-1.” J Biol Chem. 1997; 272(16):10382-10388.
[cited by applicant]
Barleon, et al., “Soluble VEGFR-1 secreted by endothelial cells and monocytes is present in human serum and plasma from healthy donors.” Angiogenesis. 2001; 4(2):143-154.
[cited by applicant]
Belgore, et al., “Plasma levels of vascular endothelial growth factor (VEGF) and its receptor, Flt-1, in haematological cancers: a comparison with breast cancer.” Am J Hematol. 2001; 66(1): 59-61.
[cited by applicant]
Belteki, Gusztav, et al. “Site-specific cassette exchange and germline transmission with mouse ES cells expressing C31 integrase.” Nature Biotechnology (2003); 21.3: 321-324.
[cited by applicant]
Bennett, et al., “AAV2 gene therapy readministration in three adults with congenital blindness.” Sci Transl Med. 2012; 4(120): 120ra15.
[cited by applicant]
Bennett, et al., “Gene therapy for retinitis pigmentosa.” Curr Opin Mol Ther. 2000; 2(4): 420-425.
[cited by applicant]
Bennett, “Immune response following intraocular delivery of recombinant viral vectors.” Gene Ther. 2003; 10(11): 977-982.
[cited by applicant]
Bennicelli, et al., “Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer.” Mol Ther. 2008; 16(3): 458-465.
[cited by applicant]
Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 66(1 ): 1-19 (1977).
[cited by applicant]
Bethke, Bruce, and Sauer, Brian. “Segmental genomic replacement by Cre-mediated recombination: genotoxic stress activation of the p53 promoter in single-copy transformants.” Nucleic Acids Research (1997); 25.14: 2828-28…
[cited by applicant]
Bhisitkul, “Vascular endothelial growth factor biology: clinical implications for ocular treatments.” Br J Ophthalmol. 2006; 90(12): 1542-1547.
[cited by applicant]
Bi, Yanzhen, et al. “Pseudo attP sites in favor of transgene integration and expression in cultured porcine cells identified by streptomyces phage phiC31 integrase.” BMC Molecular Biology (2013); 14: 20, 12 pages.
[cited by applicant]
Brinkmann, et al., “Selective retina therapy (SRT): a review on methods, techniques, preclinical and first clinical results.” Bull Soc Beige Ophtalmol. 2006; 302: 51-69.
[cited by applicant]
Brinkmann, et al., “Origin of retinal pigment epithelium cell damage by pulsed laser irradiance in the nanosecond to microsecond time regimen.” Laser Surg Med. 2000; 27: 451-464.
[cited by applicant]
Brown, et al., “Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study.” Ophthalmology. 2009; 116(1): 57-65.
[cited by applicant]
Buning, H et al., “Recent developments in adeno associated virus vector technology,” J Gene Med 2008; 10: 717-733.
[cited by applicant]
Cai, Xue, et al. “Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa.” The FASEB Journal (2010); 24.4: 1178-119…
[cited by applicant]
Calcedo, Roberto, et al. “Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses.” Journal of Infectious Diseases (2009); 199.3: 381-390.
[cited by applicant]
Calos, Michele P. “The C31 Integrase System for Gene Therapy.” Current Gene Therapy (2006); 6.6: 633-645.
[cited by applicant]
Campochiaro, et al., “Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial.” Hum Gene Ther. 2006; 17(2): 167-176.
[cited by applicant]
Campochiaro, et al., “Monitoring ocular drug therapy by analysis of aqueous samples.” Ophthalmology. 2009; 116(11): 2158-2164.
[cited by applicant]
Campochiaro, “Gene Transfer for Neovascular Age-Related Macular Degeneration.” Human Gene Therapy (2011); 22(5): 523-529.
[cited by applicant]
Campochiaro, “Molecular targets for retinal vascular diseases.” J Cell Physiol. 2007; 210(3): 575-581.
[cited by applicant]
Cao, et al., “A subretinal matrigel rat choroidal neovascularization (CNV) model and inhibition of CNV and associated inflammation and fibrosis by VEGF trap.” Invest Ophthalmol Vis Sci. 2010; 51(11): 6009-6017.
[cited by applicant]
Cayouette, et al., “Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse.” Hum Gene Ther. 1997; 8(4): 423-430.
[cited by applicant]
Chakrabarti, et al., “Normal T-cell turnover in sooty mangabeys harboring active simian immunodeficiency virus infection.” J Virol. 2000; 74(3): 1209-1223.
[cited by applicant]
Chalberg, et al., “Integration Specificity of Phage C31 Integrase in the Human Genome”, J Mol Biol. (Mar. 17, 2006); 357(1): 28-48. Epub Dec. 22, 2005.
[cited by applicant]
Chalberg, Thomas W., et al. “C31 integrase confers genomic integration and long-term transgene expression in rat retina.” Investigative Ophthalmology & Visual Science (2005); 46.6: 2140-2146.
[cited by applicant]
Chen, et al., “Use of nepafenac (Nevanac) in combination with intravitreal anti-VEGF agents in the treatment of recalcitrant exudative macular degeneration requiring monthly injections.” Clin Ophthalmol. 2010; 4:1249-12…
[cited by applicant]
Chiu, M. I., and Nathans, J. “Blue cones and cone bipolar cells share transcriptional specificity as determined by expression of human blue visual pigment-derived transgenes.” The Journal of Neuroscience (1994); 14.6: 3…
[cited by applicant]
Choi, et al., “Production of recombinant Adeno-associated viral vectors.” Curr Protoc Hum Genet. 2007; Chapter 12: Unit 12.9.doi: 10.1002/0471142905.hg1209s53.
[cited by applicant]
Chung, et al., “Angiogenesis in myocardial infarction. An acute or chronic process?” Eur Heart J. 2002; 23(20): 1604-1608.
[cited by applicant]
Cideciyan, Artur V., et al. “Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics.” Proceedings of the National Academy of Sciences (2008); 105.39: 15112-15…
[cited by applicant]
Cideciyan, et al., “Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year.” Hum Gene Ther. 2009; 20(9): 999-1004.
[cited by applicant]
Clark, et al., “Expression of clusterin/sulfated glycoprotein-2 under conditions of heat stress in rat Sertoli cells and a mouse Sertoli cell line.” J Androl. 1997; 18(3): 257-63.
[cited by applicant]
Clinical trial, A Phase I/II Controlled Dose-escalating Trial to Establish the Baseline Safety and Efficacy of a Single Subretinal Injection of rAAV.sFit-1 Into Eyes of Patients With Exudative Age-related Macular Degene…
[cited by applicant]
Clinical Trial NCT01494805, “Safety and Efficacy Study of rAAV.sFlt-1 in Patients With Exudative Age-Related Macular Degeneration (AMD).” as published first posted on Dec. 19, 2011, 7 pages, Retrieved from: https://clin…
[cited by applicant]
Clinical Trial NCT01494805, History of Changes for “Safety and Efficacy Study of rAAV.sFlt-1 in Patients With Exudative Age-Related Macular Degeneration (AMD)”, NCT01494805, Submitted Date: Dec. 15, 2011 (v1), ClinicalT…
[cited by applicant]
Clinical trial. Safety and Tolerability Study of AAV2-sFLT-1 in Patients With Neovascular Age-Related Macular Degeneration (AMD). NCT01024998. Last updated: Jan. 28, 2014.
[cited by applicant]
Comparison of L-opsin promoter to SEQ ID No. 80. Printed Feb. 2, 2017, in U.S. Appl. No. 14/660,657, 4 pages.
[cited by applicant]
Co-pending U.S. Appl. No. 14/444,347, inventor Schaffer; et al., filed Jul. 28, 2014.
[cited by applicant]
Co-pending U.S. Appl. No. 14/444,375, inventor Schaffer; et al., filed Jul. 28, 2014.
[cited by applicant]
Co-pending U.S. Appl. No. 14/606,543, inventor Schaffer; et al., filed Jan. 27, 2015.
[cited by applicant]
Co-pending U.S. Appl. No. 14/938,154, inventor Schaffer; et al., filed Nov. 11, 2015.
[cited by applicant]
Co-pending U.S. Appl. No. 15/229,699, inventor Schaffer; et al., filed Aug. 5, 2016.
[cited by applicant]
Co-pending U.S. Appl. No. 15/244,884, inventor Schaffer; et al., filed Aug. 23, 2016.
[cited by applicant]
Co-pending U.S. Appl. No. 15/244,892, inventor Schaffer; et al., filed Aug. 23, 2016.
[cited by applicant]
Co-pending U.S. Appl. No. 15/939,674, inventor Neitz, et al., filed Mar. 29, 2018.
[cited by applicant]
Csermely, et al., “The 90-kDa molecular chaperone family: structure, function, and clinical applications.” A comprehensive review. Pharmacol Ther. 1998; 79(2):129-168.
[cited by applicant]
Curtis, et al., “Risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration.” Arch Ophthalmol. 2010; 128(10): 1273-1279.
[cited by applicant]
Dalkara D., et al., “In Vivo-Directed Evolution of a New Adeno-Associated Virus for Therapeutic Outer Retinal Gene Delivery from the Vitreous,” Science Translational Medicine, 2013, vol. 5 (189), 11 pages.
[cited by applicant]
Davidson, et al., “A model system for in vivo gene transfer into the central nervous system using an adenoviral vector.” Nat Genet. 1993; 3(3): 219-223.
[cited by applicant]
Davis, et al., “Direct gene transfer into skeletal muscle in vivo: factors affecting efficiency of transfer and stability of expression.” Hum Gene Ther. 1993; 4(2): 151-159.
[cited by applicant]
Dawson, et al., “Pigment epithelium-derived factor: a potent inhibitor of angiogenesis.” Science. 1999; 285(5425): 245-248.
[cited by applicant]
De Vries, et al., “The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.” Science. 1992; 255(5047): 989-991.
[cited by applicant]
Definition of “plasmid”, Biology Dictionary, 2018, 1 page.
[cited by applicant]
Dejneka, et al., “Gene therapy and animal models for retinal disease.” Dev Ophthalmol. 2003; 37: 188-198.
[cited by applicant]
Dejneka, et al., “Gene therapy and retinitis pigmentosa: advances and future challenges.” Bioessays 2001; 23(7): 662-8.
[cited by applicant]
Deonarain, M.P., “Ligand-targeted receptor-mediated vectors for gene delivery”, Expert Opinion on Therapeutic Patents. 1998; 8: 53-69.
[cited by applicant]
Devalois, R.L. and DeValois, K.K. “A multi-stage color model.” Vision Research (1993); 33.8: 1053-1065.
[cited by applicant]
Deyle and Russell, “Adeno-associated virus vector integration.” Curr. Opin. Mol. Therapy (2009); 11 (4): 442-447.
[cited by applicant]
Diab, et al., “Angiogenic factors for the prediction of pre-eclampsia in women with abnormal midtrimester uterine artery Doppler velocimetry.” Int J Gynaecol Obstet. 2008; 102(2):146-151.
[cited by applicant]
Dudus, et al., “Persistent trans gene product in retina, optic nerve and brain after intraocular injection of rAAV.” Vision Res. 1999; 39(15): 2545-2553.
[cited by applicant]
Dull, et al., “A third-generation lentivirus vector with a conditional packaging system.” Journal of Virology (1998), 72(11):8463-8671.
[cited by applicant]
Easton, et al., “The Hsp110 and Grp170 stress proteins: newly recognized relatives of the Hsp70s.” Cell Stress Chaperones. 2000; 5(4): 276-290.
[cited by applicant]
Edelstein et al., “Gene therapy clinical trials worldwide 1989-2004—an overview”, Journal Gene Med. (2004); 6: 597-602.
[cited by applicant]
European Patent Application No. 13791695.3, Extended European Search Report dated Dec. 21, 2015, 10 pages.
[cited by applicant]
European Patent Application No. 15765668.7, Extended European Search Report dated Mar. 7, 2018, 18 pages.
[cited by applicant]
European Patent Application No. 15765668.7, Partial Supplemental European Search Report dated Nov. 10, 2017, 8 pages.
[cited by applicant]
European Patent Application No. 18198081.4, Extended European Search Report dated May 24, 2019, 11 pages.
[cited by applicant]
Excoffon et al., “Directed evolution of adeno-associated virus to an infectious respiratory virus,” PNAS, Mar. 10, 2009, vol. 106, No. 10, pp. 3865-3870.
[cited by applicant]
Ferrara, “Vascular endothelial growth factor: basic science and clinical progress.” Endocr Rev. 2004; 25(4): 581-611.
[cited by applicant]
Fong, et al., “The use and development of retroviral vectors to deliver cytokine genes for cancer therapy.” Crit Rev Ther Drug Carrier Syst. 2000; 17(1): 1-60.
[cited by applicant]
Fotsis, et al., “The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth.” Nature. 1994; 368(6468): 237-239.
[cited by applicant]
Framme, et al., “Selective targeting of the retinal pigment epithelium in rabbit eyes with a scanning laser beam.” Investigative Ophthalmology & Visual Science (2007); 48(4): 1782-1792.
[cited by applicant]
Funk, et al., “Neovascular age-related macular degeneration: intraocular cytokines and growth factors and the influence of therapy with ranibizumab.” Ophthalmology. 2009; 116(12): 2393-2399.
[cited by applicant]
Galan, et al., “Association of age-related macular degeneration with polymorphisms in vascular endothelial growth factor and its receptor.” Ophthalmology. 2010; 117(9): 1769-1774.
[cited by applicant]
Geller, et al., “An HSV-1 vector expressing tyrosine hydroxylase causes production and release of L-dopa from cultured rat striatal cells.” J Neurochem. 1995; 64(2):487-496.
[cited by applicant]
Geller, et al., “Infection of cultured central nervous system neurons with a defective herpes simplex virus 1 vector results in stable expression of
[cited by applicant]
Geller, et al., “Long-term increases in neurotransmitter release from neuronal cells expressing a constitutively active adenylate cyclase from a herpes simplex virus type 1 vector.” Proc Natl Acad Sci USA. 1993; 90(16):…
[cited by applicant]
GenBank [online], Accession No. U47119.2, “Cloning vector pCI, mammalian expression vector.” May 10, 2004—uploaded, [retrieved on Apr. 12, 2017], https://www.ncbi.nlm.nih.gov/nuccore/U47119, 2 pages.
[cited by applicant]
Gerdes, et al., “Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67.” J Immunol. 1984; 133(4):1710-1715.
[cited by applicant]
Glushakova, Lyudmyla G., et al. “Human blue-opsin promoter preferentially targets reporter gene expression to rat s-cone photoreceptors.” Investigative Ophthalmology & Visual Science (2006); 47.8: 3505-3513.
[cited by applicant]
Goldman, et al., “Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, and mortality rate.” Proc Natl Acad Sci USA. 1998; 95(15): 8795-8800.
[cited by applicant]
Goverdhana, et al., Regulatable gene expression systems for gene therapy applications: progress and future challenges. Molecular Therapy : The Journal of the American Society of Gene Therapy. 2005; 12(2): 189-211.
[cited by applicant]
Gragoudas, et al., “Pegaptanib for neovascular age-related macular degeneration.” N Engl J Med. 2004; 351(27): 2805-2816.
[cited by applicant]
Graubert, et al., “Vascular repair after menstruation involves regulation of vascular endothelial growth factor-receptor phosphorylation by sFLT-1.” Am J Pathol. 2001; 158(4): 1399-1410.
[cited by applicant]
Gray and Zolotukhin, “Design and Construction of Functional AAV Vectors.” Methods in Molecular Biology. 2011; 807: 25-46.
[cited by applicant]
Groth, Amy C., et al. “A phage integrase directs efficient site-specific integration in human cells.” Proc Natl Acad Sci U S A. (2000); 97.11: 5995-6000.
[cited by applicant]
Gunther, Karen L., et al. “A novel mutation in the short-wavelength-sensitive cone pigment gene associated with a tritan color vision defect.” Visual Neuroscience (2006); 23.3-4: 403-409.
[cited by applicant]
Hasumi, et al., “Soluble FLT-1 expression suppresses carcinomatous ascites in nude mice bearing ovarian cancer.” Cancer Res. 2002; 62(7): 2019-2023.
[cited by applicant]
Hauswirth, et al., “Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of Adeno-associated virus gene vector: short-term results of a phase I trial.” Hum Gene Ther. 2008; 19(10…
[cited by applicant]
He, et al., “Alternative splicing of vascular endothelial growth factor (VEGF)-R1 (FLT-1) pre-mRNA is important for the regulation of VEGF activity.” Mol Endocrinol. 1999; 13(4): 537-545.
[cited by applicant]
Heinis, Christian, and Johnsson, Kai. “Using peptide loop insertion mutagenesis for the evolution of proteins.” Methods Mol Biol. (2010); 634: 217-232.
[cited by applicant]
Hoess, R.H. et al. “The role of the loxP spacer region in P1 site-specific recombination.” Nucleic Acids Research (1986); 14.5: 2287-2300.
[cited by applicant]
Hoffman, et al., “Cell-mediated immune response and stability of intraocular transgene expression after adenovirus-mediated delivery.” Invest Ophthalmol Vis Sci. 1997; 38(11): 2224-2233.
[cited by applicant]
Honda, et al., “Experimental subretinal neovascularization is inhibited by adenovirus-mediated soluble VEGF/flt-1 receptor gene transfection: a role of VEGF and possible treatment for SRN in age-related macular degenera…
[cited by applicant]
Hu, et al., “Design of retroviral vectors and helper cells for gene therapy.” Pharmacol Rev. 2000; 52(4): 493-511.
[cited by applicant]
Huang, et al., “Innate immune recognition of viruses and viral vectors.” Hum Gene Ther. 2009; 20(4): 293-301.
[cited by applicant]
Ibrahim, et al., “Heat shock and arsenite induce expression of the nonclassical class I histocompatibility HLA-G gene in tumor cell lines.” Cell Stress Chaperones. 2000; 5(3): 207-218.
[cited by applicant]
Ideno, et al., “Prevention of diabetic retinopathy by intraocular soluble flt-1 gene transfer in a spontaneously diabetic rat model”. Int J Mol Med. (Jan. 2007); 19(1): 75-79.
[cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/US2010/048964, mailed Mar. 20, 2012, 14 pages.
[cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/US2013/040011, mailed Nov. 18, 2014, 48 pages.
[cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/US2013/045043, mailed Dec. 16, 2014, 9 pages.
[cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/US2015/021087, mailed Sep. 20, 2016, 8 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2010/048964, mailed Jun. 17, 2011, 23 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2013/040011, mailed Dec. 17, 2013, 57 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2013/045043, mailed Nov. 12, 2013, 11 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2015/021087, mailed Aug. 12, 2015, 12 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2016/020482, mailed Aug. 8, 2016, 12 pages.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2016/068312, mailed May 3, 2017, 22 pages.
[cited by applicant]
Invitation to Pay Additional Fees for International Application No. PCT/US2013/040011, mailed Oct. 11, 2013, 5 pages.
[cited by applicant]
Jacobs, Gerald H. “A perspective on color vision in platyrrhine monkeys.” Vision Research (1998); 38.21: 3307-3313.
[cited by applicant]
Jacobs, Gerald H., et al. “Emergence of novel color vision in mice engineered to express a human cone photopigment.” Science (2007); 315.5819: 1723-1725.
[cited by applicant]
Jacobson, et al., “Safety in nonhuman primates of ocular AA V2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis.” Hum Gene Ther. 2006; 17(8): 845-858.
[cited by applicant]
Jacobson, et al., “Safety of recombinant Adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection”, Mol Ther. (2006); 13(6):1074-1084.
[cited by applicant]
Jacobson, et al., “Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years.” Arch Ophthalmol. (2012); 130(1): 9-24.
[cited by applicant]
Johnson-Saliba and Jans, “Gene Therapy: Optimising DNA Delivery to the Nucleus”, Curr. Drug. Targets 2001; 2(4): 371-399.
[cited by applicant]
Kaplitt, M.G. et al. (1994). “Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain,” Nature Genetics 6:148-154.
[cited by applicant]
Kendall, et al., “Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR.” Biochem Biophys Res Commun. 1996; 226(2): 324-328.
[cited by applicant]
Kendall, et al., “Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor.” Proc Natl Acad Sci USA. (1993); 90(22): 10705-10709.
[cited by applicant]
Khaliq, et al., “Increased expression of placenta growth factor in proliferative diabetic retinopathy.” Lab Invest. 1998; 78(1): 109-116.
[cited by applicant]
Khani, et al., “AAV-mediated expression targeting of rod and cone photoreceptors with a human rhodopsin kinase promoter.” Investigative Ophthalmology & Visual Science. 2007; 48(9): 3954-3961.
[cited by applicant]
Kiang, et al., “Cytoprotection and regulation of heat shock proteins induced by heat shock in human breast cancer T47-D cells: role of [Ca2+]i and protein kinases.” FASEB J. 1998; 12(14): 1571-1579.
[cited by applicant]
Klein, et al., “Fifteen-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study.” Ophthalmology. 2007; 114(2): 253-262.
[cited by applicant]
Klein, et al., “The relation of cardiovascular disease and its risk factors to the 5-year incidence of age-related maculopathy: the Beaver Dam Eye Study.” Ophthalmology. 1997; 104(11): 1804-1812.
[cited by applicant]
Kliffen, et al., “Increased expression of angiogenic growth factors in age-related maculopathy.” Br J Ophthalmol. 1997; 81(2): 154-162.
[cited by applicant]
Komaromy, et al., “Targeting gene expression to cones with human cone opsin promoters in recombinant AAV.” Gene Ther. 2008; 15(14): 1049-1055.
[cited by applicant]
Komromy, Andrs M., et al. “Gene therapy rescues cone function in congenital achromatopsia.” Human Molecular Genetics (Jul. 2010); 19(13): 2581-2593. Epub Apr. 8, 2010.
[cited by applicant]
Kong, et al., “Regional suppression of tumor growth by in vivo transfer of a cDNA encoding a secreted form of the extracellular domain of the fit-1 vascular endothelial growth factor receptor.” Hum Gene Ther. 1998; 9(6)…
[cited by applicant]
Kozak, “Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes”, Cell (1986); 44(2): 283-292 (Abstract Only).
[cited by applicant]
Krysiak, et al., “Soluble vascular endothelial growth factor receptor-1 (sFLT-1) mediates downregulation of FLT-1 and prevents activated neutrophils from women with preeclampsia from additional migration by VEGF.” Circ …
[cited by applicant]
Krzystolik, et al., “Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment.” Arch Ophthalmol. 2002; 120(3):338-346.
[cited by applicant]
Kuchenbecker, James A., et al. “Topography of the long-to middle-wavelength sensitive cone ratio in the human retina assessed with a wide-field color multifocal electroretinogram.” Visual Neuroscience (2008); 25.03: 301…
[cited by applicant]
Kvanta, et al., “Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor.” Invest Ophthalmol Vis Sci. 1996; 37(9): 1929-1934.
[cited by applicant]
Kvaratskhelia, Mamuka, et al. “Molecular mechanisms of retroviral integration site selection.” Nucleic Acids Research (2014); 42.16: 10209-10225.
[cited by applicant]
Kwak, et al., “VEGF is major stimulator in model of choroidal neovascularization.” Invest Ophthalmol Vis Sci. 2000; 41(10): 3158-3164.
[cited by applicant]
La Salle, “An adenovirus vector for gene transfer into neurons and glia in the brain,” Science, Feb. 1993, 259: 988-990.
[cited by applicant]
Lai, et al., “Generation of transgenic mice with mild and severe retinal neovascularisation.” Br J Ophthalmol. 2005; 89(7): 911-916.
[cited by applicant]
Lai, et al., “Inhibition of angiogenesis by adenovirus-mediated sFlt-1 expression in a rat model of corneal neovascularization.” Hum Gene Ther. 2001; 12(10): 1299-1310.
[cited by applicant]
Lai et al. “Long-Term Evaluation of AAV-Mediated sFlt-1 Gene Therapy for Ocular Neovascularization in Mice and Monkeys.” Molecular Therapy (2005); 12:4, p. 659-668.
[cited by applicant]
Lai, et al., “Potential long-term inhibition of ocular neovascularisation by recombinant Adeno-associated virus-mediated secretion gene therapy.” Gene Ther. 2002; 9(12): 804-813.
[cited by applicant]
Lai, et al., “Preclinical safety evaluation of subretinal AAV2.sF1t-1 in non-human primates.” Gene Ther. 2012; 19(10): 999-1009. Epub Nov. 10, 2011.
[cited by applicant]
Lai, et al., “rAAV.sFIt-1 Gene Therapy Achieves Lasting Reversal of Retinal Neovascularization in the Absence of a Strong Immune Response to the Viral Vector.” Invest Ophthalmol Vis Sci. 2009; 50(9): 4279-4287.
[cited by applicant]
Lai, et al., “Recombinant Adeno-associated virus type 2-mediated gene delivery into the Rpe65-/-knockout mouse eye results in limited rescue.” Genet Vaccines Ther. 2004; 2:3, 15 pages.
[cited by applicant]
Lai, Timothy YY, et al. “The clinical applications of multifocal electroretinography: a systematic review.” Survey of Ophthalmology (2007); 52.1: 61-96.
[cited by applicant]
Lalwani, et al., “A variable-dosing regimen with intravitreal ranibizumab for neovascular age- related macular degeneration: year 2 of the PrONTO Study.” Am J Ophthalmol. 2009; 148(1): 43-58.
[cited by applicant]
Langer, Stephen J., et al. “A genetic screen identifies novel noncompatible loxP sites.” Nucleic Acids Research (2002); 30.14: 3067-3077.
[cited by applicant]
Lavinksy, D. et al., “Modulation of transgene expression in retinal gene therapy by selective laser treatment.” Investigative Ophthalmology & Visual Science. 2013; 54(3): 1873-1880.
[cited by applicant]
Le Meur, et al., “Postsurgical assessment and long-term safety of recombinant adeno-associated virus-mediated gene transfer into the retinas of dogs and primates.” Arch Ophthalmol. 2005; 123(4): 500-506.
[cited by applicant]
Le Meur, et al., “Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium.” Gene Ther. 2007; 14(4): 292-303.
[cited by applicant]
Lebherz, et al., “Novel AAV serotypes for improved ocular gene transfer.” J Gene Med. 2008; 10(4): 375-382.
[cited by applicant]
Lee and Saito, “Role of nucleotide sequences of loxP spacer region in Cre-mediated recombination,” Gene. Aug. 17, 1998;216(1):55-65.
[cited by applicant]
Levine, et al., “Circulating angiogenic factors and the risk of preeclampsia.” N Engl J Med. 2004; 350(7): 672-683.
[cited by applicant]
Li, et al., “Cone-specific expression using a human red opsin promoter in recombinant AAV.” Vision Res. 2008; 48(3): 332-338.
[cited by applicant]
Li, et al., “Gene therapy following subretinal AAV5 vector delivery is not affected by a previous intravitreal AAV5 vector administration in the partner eye.” Mol Vis. 2009; 15: 267-275.
[cited by applicant]
Li, et al., “Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential.” Mol Vis. 2008; 14: 1760-1769.
[cited by applicant]
Lieber, et al., “Integrating adenovirus-Adeno-associated virus hybrid vectors devoid of all viral genes.” J Virol. 1999; 73(11): 9314-9324.
[cited by applicant]
Lindenberg, Thomas, et al. “Cyclic summation versus m-sequence technique in the multifocal ERG.” Graefe's Archive for Clinical and Experimental Ophthalmology (2003); 241.6: 505-510.
[cited by applicant]
Liu, et al., “Gene therapy for ocular diseases.” Br J Ophthalmol. 2011; 95(5): 604-612.
[cited by applicant]
Liu, et al., “Soluble Fms-like tyrosine kinase-1 expression inhibits the growth of multiple myeloma in nude mice.” Acta Biochim Biophys Sin (Shanghai). 2007; 39(7): 499-506.
[cited by applicant]
Liu, Xiaomei, Han Ping, and Chun Zhang. “Rapid establishment of a HEK 293 cell line expressing FVIII-BDD using AAV site-specific integration plasmids.” BMC Research Notes (2014); 7: 626, 6 pages.
[cited by applicant]
Lopez, et al., “Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membran…
[cited by applicant]
Lu, et al., “Complete correction of hemophilia A with adeno-associated viral vectors containing a full-size expression cassette.” Hum Gene Ther. (2008); 19(6):648-654. doi: 10.1089/hum.2007.0182.
[cited by applicant]
Lukason, et al., “Inhibition of choroidal neovascularization in a nonhuman primate model by intravitreal administration of an AAV2 vector expressing a novel anti-VEGF molecule.” Mol Ther. (Feb. 2011); 19(2): 260-265. Ep…
[cited by applicant]
Lundstrom, “Alphavirus vectors: applications for DNA vaccine production and gene expression.” Intervirology. 2000; 43(4-6): 247-257.
[cited by applicant]
Luo and Saltzman, “Synthetic DNA delivery systems”, Nature Biotechnol. 2000; 18(1): 33-37.
[cited by applicant]
Luthert, et al., “Photoreceptor rescue.” Eye (Lond). 1998; 12(Pt 3b): 591-596.
[cited by applicant]
MacLachlan, et al., “Preclinical safety evaluation of AAV2-sFLT01—a gene therapy for age-related macular degeneration.” Mol Ther. 2011; 19(2): 326-334. Epub Nov. 30, 2010.
[cited by applicant]
Mae, et al., “Gene transfer of the vascular endothelial growth factor receptor flt-1suppresses pulmonary metastasis associated with lung growth.” Am J Respir Cell Mol Biol. 2005; 33(6): 629-635.
[cited by applicant]
Maguire, A.M. et al. (2008). “Safety and efficacy of gene transfer for Leber's congenital amaurosis,” N. Engl J Med 358:2240-2248.
[cited by applicant]
Maguire, et al., “Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial.” Lancet. 2009; 374(9701): 1597-1605.
[cited by applicant]
Mahasreshti, et al., “Adenovirus-mediated soluble FLT-1 gene therapy for ovarian carcinoma.” Clin Cancer Res. 2001; 7(7): 2057-2066.
[cited by applicant]
Mahasreshti, et al., “Intravenous delivery of adenovirus-mediated soluble FLT-1 results in liver toxicity.” Clin Cancer Res. 2003; 9(7): 2701-2710.
[cited by applicant]
Maheshri, Narendra, et al. “Directed evolution of adeno-associated virus yields enhanced gene delivery vectors.” Nature Biotechnology (2006); 24.2: 198-204.
[cited by applicant]
Makous, Walter. “Comment on “emergence of novel color vision in mice engineered to express a human cone photopigment”.” Science (2007); 318.5848: 196b-196b.
[cited by applicant]
Malamos, et al., “Correlation of high-definition optical coherence tomography and fluorescein angiography imaging in neovascular macular degeneration.” Invest. Ophthalmol Vis Sci. 2009; 50(10): 4926-4933.
[cited by applicant]
Mancuso, et al., “Colorblindness Cure: Gene Therapy Confers a New Sensation”, Investigative Opthamology & Visual Science (2008), 49: E-Abstract 3252 (Meeting Abstract).
[cited by applicant]
Mancuso et al. “Gene therapy for red-green colour blindness in adult primates.” Nature (2009); 461:7265, p. 784-787.
[cited by applicant]
Mancuso et al., “Gene therapy treatment of color blindness in adult primates.” Journal of Vision (2007); 7(15): 15a. (Abstract).
[cited by applicant]
Mancuso, et al., “Recombinant Adeno-associated virus targets passenger gene expression to cones in primate retina”, Journal of the Optical Society of America A (2007); 24(5): 1411-1416.
[cited by applicant]
Mancuso, K., et al. “Progress in Developing a Gene Therapy Approach for Treating Color Blindness.” Investigative Ophthalmology & Visual Science 46.13 (2005): 4565-4565 & 2005 Annual Meeting of the Association for Resear…
[cited by applicant]
Mancuso, Katherine, et al. “An adaptation of the Cambridge Colour Test for use with animals.” Visual Neuroscience (2006); 23.3-4: 695-701.
[cited by applicant]
Manno, et al., “Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.” Nat Med. 2006; 12(3): 342-347.
[cited by applicant]
Mao, Yanxiong, et al. “Persistent Suppression of Ocular Neovascularization with Intravitreal Administration of AAVrh. 10 Coding for Bevacizumab.” Human Gene Therapy (2011); 22(12): 1525-1535.
[cited by applicant]
Martin et al., “Gene delivery to the eye using adeno-associated viral vectors”, Methods (2002); 28: 267-275.
[cited by applicant]
Mauck, et al., “Longitudinal in vivo Characterization of Expression of Viral Delivered Genes for L-opsin and Green Fluorescent Protein in Cone Photoreceptors of Gerbils.” Investigative Ophthalmology & Visual Science (20…
[cited by applicant]
Mauck, Matthew C., et al. “Longitudinal evaluation of expression of virally delivered transgenes in gerbil cone photoreceptors.” Visual Neuroscience (2008); 25(3): 273-282.
[cited by applicant]
Maynard, et al., “Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.” J Clin Invest. 2003; 111(5): 649-658.
[cited by applicant]
McLeod, Maureen, et al. “Identification of the crossover site during FLP-mediated recombination in the
[cited by applicant]
Merigan, et al., “Tracking Transfection of Macaque Retinal Ganglion Cells With AAV2 Viral Vectors; In vivo Imaging Reveals Differences Between Two Promoters.” ARVO Annual Meeting Abstract (May 2008); Investigative Ophth…
[cited by applicant]