Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration

被引：116

作者：

Constable, Ian J. ^{[1
,2
,3
]}

Pierce, Cora M. ^{[1
]}

Lai, Chooi-May ^{[1
,3
]}

Magno, Aaron L. ^{[1
]}

Degli-Esposti, Mariapia A. ^{[1
,3
]}

French, Martyn A. ^{[4
,5
]}

McAllister, Ian L. ^{[1
,2
,3
]}

Butler, Steve ^{[6
]}

Barone, Samuel B. ^{[6
]}

Schwartz, Steven D. ^{[7
]}

Blumenkranz, Mark S. ^{[8
]}

Rakoczy, Elizabeth P. ^{[1
,3
]}

机构：

[1] Lions Eye Inst, Nedlands, WA, Australia

[2] Sir Charles Gairdner Hosp, Nedlands, WA, Australia

[3] Univ Western Australia, Ctr Ophthalmol & Visual Sci, Crawley, WA, Australia

[4] Univ Western Australia, Sch Pathol & Lab Med, Crawley, WA, Australia

[5] Univ Western Australia, Dept Clin Immunol, Crawley, WA, Australia

[6] Avalanche Biotechnol Inc, Menlo Pk, CA USA

[7] Univ Calif Los Angeles, Los Angeles, CA 90024 USA

[8] Stanford Dept Ophthalmol, Byers Eye Inst, Palo Alto, CA USA

来源：

EBIOMEDICINE | 2016年 / 14卷

基金：

英国医学研究理事会;

关键词：

Wet age related macular degeneration; AAV.sFLT-1; Gene therapy; Clinical trial; GENE-THERAPY; OCULAR NEOVASCULARIZATION; ADENOASSOCIATED VIRUS; CONGENITAL AMAUROSIS; IMMUNE-RESPONSE; VEGF-TRAP; INHIBITION; ANGIOGENESIS; RANIBIZUMAB; EXPRESSION;

D O I：

10.1016/j.ebiom.2016.11.016

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: We present the results of a Phase 2a randomized controlled trial investigating the safety, and secondary endpoints of subretinal rAAV.sFLT-1 gene therapy in patientswith active wet age-related macular degeneration (wAMD). Methods: All patients (n = 32), (ClinicalTrials.gov;NCT01494805), received ranibizumab injections at baseline and week 4, and thereafter according to prespecified criteria. Patients in the gene therapy group (n = 21) received rAAV.sFLT-1 (1 x 10(11) vg). All patients were assessed every 4 weeks to the week 52 primary endpoint. Findings: Ocular adverse events (AEs) in the rAAV.sFLT-1 group were mainly procedure related and self-resolved. All 11 phakic patients in the rAAV. sFLT-1 group showed progression of cataract following vitrectomy. No systemic safety signals were observed and none of the serious AEs were associated with rAAV. sFLT-1. AAV2 capsid was not detected and rAAV.sFLT-1 DNA was detected transiently in the tears of 13 patients. ELISPOT analysis did not identify any notable changes in T-cell response. In the rAAV.sFLT-1 group 12 patients had neutralizing antibodies (nAb) to AAV2. There was no change in sFLT-1 levels in bodily fluids. In the rAAV.sFLT-1 group, Best Corrected Visual Acuity (BCVA) improved by a median of 1.0 (IQR: -3.0 to 9.0) Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline compared to a median of -5.0 (IQR: -17.5 to 1.0) ETDRS letters change in the control group. Twelve (57%) patients in the rAAV.sFLT-1 group maintained or improved vision compared to 4 (36%) in the control group. The median number of ranibizumab retreatments was 2.0 (IQR: 1.0 to 6.0) for the gene therapy group compared to 4.0 (IQR: 3.5 to 4.0) for the control group. Interpretation rAAV.sFLT-1 combined with the option for co-treatment appears to be a safe and promising approach to the treatment of wAMD. (C) 2016 The Authors. Published by Elsevier B.V.

引用

页码：168 / 175

页数：8

共 31 条

[31] AAV-Mediated Gene Therapy for Choroideremia: Preclinical Studies in Personalized Models [J].

Vasireddy, Vidyullatha ;

Mills, Jason A. ;

Gaddameedi, Rajashekhar ;

Basner-Tschakarjan, Etiena ;

Kohnke, Monika ;

Black, Aaron D. ;

Alexandrov, Krill ;

Zhou, Shangzhen ;

Maguire, Albert M. ;

Chung, Daniel C. ;

Mac, Helen ;

Sullivan, Lisa ;

Gadue, Paul ;

Bennicelli, Jeannette L. ;

French, Deborah L. ;

Bennett, Jean .

PLOS ONE, 2013, 8 (05)

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