June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
One-year analysis of sFlt-1 and VEGF proteins and immunological markers in the bodily fluids of subjects participating in the Phase I rAAV.sFlt-1 trial.
Author Affiliations & Notes
  • Elizabeth P Rakoczy
    Centre for Ophthalmol & Visual Sciences, The University of Western Australia, Nedlands, WA, Australia
  • Chooi-May Lai
    Centre for Ophthalmol & Visual Sciences, The University of Western Australia, Nedlands, WA, Australia
  • Aaron Magno
    Centre for Ophthalmol & Visual Sciences, The University of Western Australia, Nedlands, WA, Australia
  • Matthew Wikstrom
    Centre for Ophthalmol & Visual Sciences, The University of Western Australia, Nedlands, WA, Australia
  • Martyn French
    School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, WA, Australia
  • Steven D Schwartz
    Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA
  • Mark S Blumenkranz
    Byers Eye Institute, Stanford University, Palo Alto, CA
  • Thomas Walter Chalberg
    Avalanche Biotechnologies, Palo Alto, CA
  • Mariapia Degli-Espoti
    Centre for Ophthalmol & Visual Sciences, The University of Western Australia, Nedlands, WA, Australia
  • Ian J Constable
    Centre for Ophthalmol & Visual Sciences, The University of Western Australia, Nedlands, WA, Australia
  • Footnotes
    Commercial Relationships Elizabeth Rakoczy, Avalanche Biotechnologies (C), Avalanche Biotechnologies (C), Avalanche Biotechnologies (P), Avalanche Biotechnologies (P); Chooi-May Lai, Avalanche Biotechnologies (F), Avalanche Biotechnologies (P); Aaron Magno, Avalanche Biotechnologies (F); Matthew Wikstrom, None; Martyn French, None; Steven Schwartz, Avalanche Biotechnologies (I); Mark Blumenkranz, Avalanche Biotechnologies (I); Thomas Chalberg, Avalanche Biotechnologies (E), Avalanche Biotechnologies (E), Avalanche Biotechnologies (I), Avalanche Biotechnologies (P); Mariapia Degli-Espoti, None; Ian Constable, Avalanche Biotechnologies (F), Avalanche Biotechnologies (P)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 1281. doi:https://doi.org/
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      Elizabeth P Rakoczy, Chooi-May Lai, Aaron Magno, Matthew Wikstrom, Martyn French, Steven D Schwartz, Mark S Blumenkranz, Thomas Walter Chalberg, Mariapia Degli-Espoti, Ian J Constable; One-year analysis of sFlt-1 and VEGF proteins and immunological markers in the bodily fluids of subjects participating in the Phase I rAAV.sFlt-1 trial.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1281. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To assess whether subretinal injection of rAAV.sFlt-1 influences sFlt-1 and VEGF levels in the tears, saliva, blood, or urine of subjects participating in the Phase 1 trial up to one year post-treatment.

Methods: A total of 8 subjects with wet AMD were enrolled, including 2 control subjects and 6 subjects treated with rAAV.sFlt-1 (3 low dose: 10E10 vg and 3 high dose: 10E11 vg) via subretinal injection. Assays for sFlt-1 and VEGF proteins in serum, urine and saliva were conducted at regular intervals. ELISAs were also performed at the same time points to detect both total anti-AAV antibodies and neutralizing antibodies in serum. The systemic immune response to rAAV.sFlt-1 was also monitored at these intervals via ELISpot on peripheral blood mononuclear cells.

Results: sFlt-1 levels averaged 53 pg/ml in serum (range 0-432 pg/ml), 44 pg/ml in urine (range 0-438), and 364 pg/ml in saliva (range 0-2338 pg/ml). There was no correlation in sFlt-1 levels within subjects among different fluids measured. There was no elevation of sFlt-1 levels observed in serum, saliva, blood, or urine following subretinal injection of rAAV.sFlt-1. In rAAV.sFlt-1 treated subjects, VEGF levels averaged 312 pg/ml in serum at baseline (169-443pg/ml) and 247pg/ml (range 73-546 pg/ml) at 1 year (p<0.4684). At baseline, three subjects (1 treated and 2 controls) tested positive for neutralizing antibodies against AAV2. Neutralizing antibodies remained unchanged in 5/6 subjects and increased in one subject at Week 3. Anti-AAV T-cell immunity was measured using IFN-g ELISpot, which remained unchanged in 5/6 subjects and one subject showed transient elevation. There was no correlation between either neutralizing antibody titres or ELISpot and clinical outcome. Subretinal injection of rAAV.sFLT-1 was highly reproducible. Most adverse events were mild, none were related to gene therapy. There was no evidence of retinal atrophy.

Conclusions: Following rAAV.sFLT-1 therapy there was no statistically significant change in sFLT-1 or VEGF levels up to 1 year post treatment.These results suggest that subretinal injection of rAAV.sFlt-1 does not alter VEGF and sFlt-1 protein levels outside of the eye and that the immune response is limited and not related to any clinical observations. These result support further research of gene therapy as a potential treatment for wet AMD.

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