Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial

Rakoczy, Elizabeth; Lai, Chooi-May; Magno, Aaron L.; Wikström, Matthew E.; French, Martyn A.; Pierce, Cora M.; Schwartz, Steven D.; Blumenkranz, Mark S.; Chalberg, Thomas W.; Degli-Esposti, Mariapia A.; Constable, Ian J.

doi:10.1016/s0140-6736(15)00345-1

Cited by 162 publications

(114 citation statements)

References 51 publications

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“…The design and methods of the study were previously described in detail (Rakoczy et al, 2015) and they are summarized as follows:…”

Section: Methodsmentioning

confidence: 99%

“…It has been reported that serum sFLT-1 is lower in wAMD patients (Uehara et al, 2015) and that sFLT-1 alone is sufficient to confer protection against choroidal neovascularization (CNV) in rodent and primate models (Lai et al, 2001, Lai et al, 2012, Lai et al, 2009, Lai et al, 2005, Lai et al, 2002, Rakoczy et al, 2015). Recombinant vector mediated gene delivery using subretinal injection of rAAV.sFLT-1 has been one approach used to demonstrate this (Lai et al, 2001, Lai et al, 2012, Lai et al, 2009, Lai et al, 2005, Lai et al, 2003, Lai et al, 2002, Rakoczy et al, 2015). This allows for the vector to be placed directly adjacent to the retinal pigment epithelial (RPE) cells and photoreceptors, enabling uptake and transduction of the viral vector.…”

Section: Introductionmentioning

confidence: 99%

“…We previously published our findings on the safety of rAAV.sFLT-1 administered subretinally to 6 patients with advanced wAMD in a Phase 1 trial (Rakoczy et al, 2015) (www.youtube.com/watch?v=CUiSFAi2_EY). Here, we present the results of our Phase 2a randomized clinical trial, investigating the safety, immunologic and other secondary endpoints of rAAV.sFLT-1 gene therapy delivered subretinally to 21 patients with active wAMD compared to 11 control patients.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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BackgroundWe 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).MethodsAll 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 × 1011 vg). All patients were assessed every 4 weeks to the week 52 primary endpoint.FindingsOcular 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.FundingNational Health and Medical Research Council of Australia (AP1010405), Lions Eye Institute, Perth Australia, Avalanche Biotechnologies, Menlo Pk, CA, USA.

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“…The design and methods of the study were previously described in detail (Rakoczy et al, 2015) and they are summarized as follows:…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Conditional knockout of Vegf in RPE cells leads to loss of the choriocapillaris and retinal atrophy (58), but it is unlikely that complete elimination of intercellular VEGF signaling can be achieved without targeted gene disruption, and no retinal damage occurred in mice after transgenic expression of a potent VEGF-neutralizing protein for up to 7 months (59) or prolonged blockade of VEGFRs (60). If it were possible to cause retinal atrophy from suppression of VEGF, one would expect it to occur after subretinal injection of an AAV vector expressing a VEGF-binding protein, because RPE cells are strongly transduced by AAV vectors, but this was not observed (61).…”

Section: Discussionmentioning

confidence: 99%

Reversible retinal vessel closure from VEGF-induced leukocyte plugging

Liu¹,

Shen²,

Fortmann³

et al. 2017

JCI Insight

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“…In wet AMD patients, gene therapy with recombinant adeno-associated vectors delivered subretinally has been reported to be safe and well tolerated, and it can be used as a potential longterm treatment option for wet AMD [83,84] .…”

Section: Gene Therapymentioning

confidence: 99%

Subretinal Injection: A Review on the Novel Route of Therapeutic Delivery for Vitreoretinal Diseases

Peng

Tang

Zhou³

2017

Ophthalmic Res

138

117

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Compared to intravitreal injection, subretinal injection has more direct effects on the targeting cells in the subretinal space, which provides a new therapeutic method for vitreoretinal diseases, especially when gene therapy and/or cell therapy is involved. To date, subretinal delivery has been widely applied by scientists and clinicians as a more precise and efficient route of ocular drug delivery for gene therapies and cell therapies including stem cells in many degenerative vitreoretinal diseases, such as retinitis pigmentosa, age-related macular degeneration, and Leber's congenital amaurosis. However, clinicians should be aware of adverse events and possible complications when performing subretinal delivery. In the present review, the subretinal injection used in vitreoretinal diseases for basic research and clinical trials is summarized and described. Different methods of subretinal delivery, as well as its benefits and challenges, are also briefly introduced.

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Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial

Cited by 162 publications

References 51 publications

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

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

Reversible retinal vessel closure from VEGF-induced leukocyte plugging

Subretinal Injection: A Review on the Novel Route of Therapeutic Delivery for Vitreoretinal Diseases

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