Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration
- PMID: 27865764
- PMCID: PMC5161436
- DOI: 10.1016/j.ebiom.2016.11.016
Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration
Abstract
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 patients with 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 (1×1011vg). All patients were assessed every 4weeks 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.
Funding: National Health and Medical Research Council of Australia (AP1010405), Lions Eye Institute, Perth Australia, Avalanche Biotechnologies, Menlo Pk, CA, USA.
Keywords: AAV.sFLT-1; Clinical trial; Gene therapy; Wet age related macular degeneration.
Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.
Figures
![Fig. 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5161436/bin/gr1.gif)
![Fig. 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5161436/bin/gr2.gif)
![Fig. 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5161436/bin/gr3.gif)
![Fig. 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5161436/bin/gr4.gif)
![Fig. 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5161436/bin/gr5.gif)
Similar articles
-
Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration.Am J Ophthalmol. 2019 Aug;204:113-123. doi: 10.1016/j.ajo.2019.03.006. Epub 2019 Mar 13. Am J Ophthalmol. 2019. PMID: 30878487 Clinical Trial.
-
Gene therapy for age-related macular degeneration.Expert Opin Biol Ther. 2017 Oct;17(10):1235-1244. doi: 10.1080/14712598.2017.1356817. Epub 2017 Jul 20. Expert Opin Biol Ther. 2017. PMID: 28726562 Review.
-
Gene Therapy in Neovascular Age-related Macular Degeneration: Three-Year Follow-up of a Phase 1 Randomized Dose Escalation Trial.Am J Ophthalmol. 2017 May;177:150-158. doi: 10.1016/j.ajo.2017.02.018. Epub 2017 Feb 27. Am J Ophthalmol. 2017. PMID: 28245970 Clinical Trial.
-
Guidelines for the Management of Wet Age-Related Macular Degeneration: Recommendations from a Panel of Greek Experts.Adv Ther. 2016 May;33(5):715-26. doi: 10.1007/s12325-016-0332-7. Epub 2016 Apr 26. Adv Ther. 2016. PMID: 27116423 Free PMC article. Review.
-
Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial.Lancet. 2015 Dec 12;386(10011):2395-403. doi: 10.1016/S0140-6736(15)00345-1. Epub 2015 Sep 30. Lancet. 2015. PMID: 26431823 Clinical Trial.
Cited by
-
Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model.Mol Ther Methods Clin Dev. 2024 Mar 22;32(2):101242. doi: 10.1016/j.omtm.2024.101242. eCollection 2024 Jun 13. Mol Ther Methods Clin Dev. 2024. PMID: 38605811 Free PMC article.
-
Adeno-associated virus as a delivery vector for gene therapy of human diseases.Signal Transduct Target Ther. 2024 Apr 3;9(1):78. doi: 10.1038/s41392-024-01780-w. Signal Transduct Target Ther. 2024. PMID: 38565561 Free PMC article. Review.
-
Beyond Vision: An Overview of Regenerative Medicine and Its Current Applications in Ophthalmological Care.Cells. 2024 Jan 17;13(2):179. doi: 10.3390/cells13020179. Cells. 2024. PMID: 38247870 Free PMC article. Review.
-
Recent Advances in Imaging Macular Atrophy for Late-Stage Age-Related Macular Degeneration.Diagnostics (Basel). 2023 Dec 10;13(24):3635. doi: 10.3390/diagnostics13243635. Diagnostics (Basel). 2023. PMID: 38132220 Free PMC article. Review.
-
Safety and Efficacy of Adeno-Associated Viral Gene Therapy in Patients With Retinal Degeneration: A Systematic Review and Meta-Analysis.Transl Vis Sci Technol. 2023 Nov 1;12(11):24. doi: 10.1167/tvst.12.11.24. Transl Vis Sci Technol. 2023. PMID: 37982768 Free PMC article.
References
-
- Bennett J., Ashtari M., Wellman J., Marshall K.A., Cyckowski L.L., Chung D.C., Mccague S., Pierce E.A., Chen Y., Bennicelli J.L., Zhu X., Ying G.S., Sun J., Wright J.F., Auricchio A., Simonelli F., Shindler K.S., Mingozzi F., High K.A., Maguire A.M. AAV2 gene therapy readministration in three adults with congenital blindness. Sci. Transl. Med. 2012;4:120ra15. - PMC - PubMed
-
- Blankenship G.W., Machemer R. Long-term diabetic vitrectomy results. Report of 10 year follow-up. Ophthalmology. 1985;92:503–506. - PubMed
-
- Bouck N. PEDF: anti-angiogenic guardian of ocular function. Trends Mol. Med. 2002;8:330–334. - PubMed
-
- Congdon N., O'Colmain B., Klaver C.C., Klein R., Munoz B., Friedman D.S., Kempen J., Taylor H.R., Mitchell P., Eye Diseases Prevalence Research G. Causes and prevalence of visual impairment among adults in the United States. Arch. Ophthalmol. 2004;122:477–485. - PubMed
Publication types
MeSH terms
Substances
Associated data
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical