G Alex Ochakovski1,2, Tobias Peters3, Stylianos Michalakis4, Barbara Wilhelm3, Bernd Wissinger2, Martin Biel4, K Ulrich Bartz-Schmidt1, M Dominik Fischer1,2,3,5. 1. University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany. 2. Institute for Ophthalmic Research, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany. 3. STZ eyetrial at the Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany. 4. Center for Integrated Protein Science Munich CiPSM at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-University of Munich, Munich, Germany. 5. Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom.
Abstract
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.
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.
Authors: Felix F Reichel; Daniyar L Dauletbekov; Reinhild Klein; Tobias Peters; G Alex Ochakovski; Immanuel P Seitz; Barbara Wilhelm; Marius Ueffing; Martin Biel; Bernd Wissinger; Stylianos Michalakis; Karl Ulrich Bartz-Schmidt; M Dominik Fischer Journal: Mol Ther Date: 2017-08-31 Impact factor: 11.454
Authors: Zhenxi Song; Liangyu Xu; Jiang Wang; Reza Rasti; Ananth Sastry; Jianwei D Li; William Raynor; Joseph A Izatt; Cynthia A Toth; Lejla Vajzovic; Bin Deng; Sina Farsiu Journal: Am J Ophthalmol Date: 2020-07-21 Impact factor: 5.258
Authors: Sanford L Boye; Shreyasi Choudhury; Sean Crosson; Giovanni Di Pasquale; Sandra Afione; Russell Mellen; Victoria Makal; Kaitlyn R Calabro; Diego Fajardo; James Peterson; Hangning Zhang; Matthew T Leahy; Colin K Jennings; John A Chiorini; Ryan F Boyd; Shannon E Boye Journal: Mol Ther Date: 2020-04-11 Impact factor: 12.910