Subretinal Injection for Gene Therapy Does Not Cause Clinically Significant Outer Nuclear Layer Thinning in Normal Primate Foveae

iovs, 58:4, 155–4160. DOI:10.1167/iovs.17-22402
iovs, online article

Purpose: Despite ever-growing adoption of subretinal (SRi) and intravitreal injections (IVTi) in ocular gene therapy trials, concerns regarding possible deleterious effects of the SRi on the outer retina are yet to be addressed. SRi offers several advantages over IVTi, such as a better photoreceptor transduction efficiency and a limited off-target exposure. We assessed structural changes in the outer retina in nonhuman primates following either SRi or IVTi of a gene therapeutic or control solution and compared both techniques in a noninferiority analysis.

Methods: In a toxicology study, 22 cynomolgus monkeys underwent single intraocular injections with rAAV2/8 or vehicle; 18 animals received SRi, 4 animals received IVTi. Outer nuclear layer (ONL) thickness change on optical coherence tomography was used for a noninferiority analysis. Preservation of the physiological foveal bulge was used as a secondary outcome measure.

Results: The average ONL change from baseline after 2 weeks was −6.54 ± 5.16 (mean ± SD μm) and +1.50 ± 4.36 for SRi and IVTi groups accordingly. At 13 weeks, the SRi group maintained a difference of −6.54 ± 9.66 while IVTi group gained +1.00 ± 4.24. The ellipsoid zone line was transiently lost after SRi and completely recovered by 13 weeks in 77% of eyes. One SRi case resulted in subfoveal pigment accumulation and 39% ONL thinning.

Conclusions: Despite limited ONL thinning following SRi, the observed effect was under the predefined clinical significance threshold. The SRi has proven not to be inferior to the IVTi in terms of ONL thickness loss and estimated loss of visual acuity.

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MPI of Biochemistry