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Guy Alex Ochakovski, Tobias Peters, Stylianos Michalakis, Barbara Wilhelm, K. Ulrich Bartz-Schmidt, M Dominik Fischer; Non-inferiority of subretinal versus intravitreal injection regarding photoreceptor layer thickness. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4100.
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© ARVO (1962-2015); The Authors (2016-present)
Despite ever growing adoption of subretinal (SR) and intravitreal (IVT) injection methods for vector delivery in ocular gene therapy trials, concerns regarding the SR approach in terms of possible deleterious effects on the outer retina are yet to be cleared. We tested the SR injection for quantifiable and qualitative structural changes in the outer retina and compared them for non-inferiority to the IVT approach in non-human primates.
In a fully GLP compliant toxicology study, 22 cynomolgus monkeys (ages 4-5, 11 male) underwent single intraocular injections with rAAV2/8 or vehicle. 18 animals received SR injections with vehicle (n = 6) or vector (n = 12), 4 animals received vector as IVT injection. Optical coherence tomography was used to visualise retinal layers before and at two timepoints after the injection (2 and 13 weeks). Outer nuclear layer (ONL) thickness was used as outcome measure to quantify change from baseline for a non-inferiority analysis. Clinical significance threshold for inferiority (M1 value) was set to an ONL reduction equivalent of three line vision loss based on previous studies (Matsumoto et al., Am J Ophthalmol. 148(1):105, 2009). Preservation of the physiological elongation of photoreceptor outer segments in the fovea (foveal bulge) was used as a secondary, qualitative measure of visual outcome.
In the SR group the average ONL change from baseline after 2 weeks was -6.54 ± 5.16µm (mean±s.d). In the IVT group the average change at 2 weeks was +1.50 ± 4.36µm. At 13 weeks, the SR group maintained a difference of -6.54 ± 9.66µm from baseline while IVT group gained +1.00 ± 4.24µm in ONL thickness on average. The foveal bulge was preserved in 9 out of 13 eyes (69%) in the SR group and in all eyes in the IVT group.
The SR injection has proven not to be inferior in a clinically significant manner to the IVT injection in terms of ONL thickness loss and estimated VA losses. Although SR injection was shown to be followed by some limited degree of ONL thinning, the observed effect including the 95% confidence intervals were under the predefined clinical significance threshold both after 2 and 13 weeks.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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