Dose-Dependent Progression of Chorioretinal Atrophy at the Injection Site After Subretinal Injection of rAAV2/8 in Nonhuman Primates

IF 3.2 Q1 OPHTHALMOLOGY Ophthalmology science Pub Date : 2024-03-15 DOI:10.1016/j.xops.2024.100516

Immanuel P. Seitz MD , Fabian Wozar MD , G. Alex Ochakovski , Felix F. Reichel MD , Faik Gelisken MD , K. Ulrich Bartz-Schmidt MD , Tobias Peters MD , M. Dominik Fischer MD, PhD

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Abstract

Objective

Progressive retinal atrophy has been described after subretinal gene therapy utilizing the adeno-associated virus (AAV) vector platform. To elucidate whether this atrophy is a consequence of inherent properties of AAV, or if it is related to the surgical trauma of subretinal delivery, we analyzed data from an Investigational New Drug–enabling study for PDE6A gene therapy in nonhuman primates.

Design

Animal study (nonhuman primates), retrospective data analysis.

Subjects

Forty eyes of 30 healthy nonhuman primates (macaca fascicularis) were included in the analysis. Two AAV dose levels (low: 1x10E11, high: 1x10E12) were compared with sham injection (balanced saline solution; BSS). Twenty untreated eyes were not analyzed.

Methods

Animals were treated with a sutureless 23G vitrectomy and single subretinal injections of AAV.PDE6A and/or BSS. The follow-up period was 12 weeks. Atrophy development was followed using fundus autofluorescence (AF), OCT, fluorescence angiography, and indocyanine green angiography.

Main Outcome Measures

Area [mm²] of retinal pigment epithelium atrophy on AF. Presence of outer retinal atrophy on optical coherence tomography. Area [mm²] of hyperfluorescence in fluorescence angiography and hypofluorescence in indocyanine green angiography.

Results

Progressive atrophy at the injection site developed in 54% of high-dose-treated, 27% of low-dose-treated, and 0% of sham-treated eyes. At the end of observation, the mean ± SD area of atrophy in AF was 1.19 ± 1.75 mm², 0.25 ± 0.50 mm², and 0.0 ± 0.0 mm², respectively (sham × high dose: P = 0.01). Atrophic lesions in AF (P = 0.01) and fluorescence angiography (P = 0.02) were significantly larger in high-dose-treated eyes, compared with sham-treated eyes. Rate of progression in high-dose-treated eyes was 4.1× higher compared with low-dose-treated eyes.

Conclusion

Subretinal injection of AAV.PDE6A induced dose-dependent, progressive retinal atrophy at the site of injection. Findings from multimodal imaging were in line with focal, transient inflammation within the retina and choroid and secondary atrophy. Atrophic changes after gene therapy with AAV-based vector systems are not primarily due to surgical trauma and increase with the dose given.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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非人灵长类动物视网膜下注射 rAAV2/8 后注射部位脉络膜视网膜萎缩的进展与剂量有关

目的有报道称，利用腺相关病毒（AAV）载体平台进行视网膜下基因治疗后会出现进行性视网膜萎缩。为了弄清这种萎缩是 AAV 固有特性的结果，还是与视网膜下给药的手术创伤有关，我们分析了在非人灵长类动物中进行的 PDE6A 基因治疗新药授权研究的数据。两种 AAV 剂量水平（低：1x10E11，高：1x10E12）与假注射（平衡盐溶液；BSS）进行了比较。方法对动物进行无缝线 23G 玻璃体切除术和单次 AAV.PDE6A 和/或 BSS 视网膜下注射。随访期为 12 周。主要结果测量AF上视网膜色素上皮萎缩的面积[mm2]。光学相干断层扫描显示视网膜外层萎缩。荧光血管造影中高荧光和吲哚青绿血管造影中低荧光的面积[mm2]。结果 54%的高剂量治疗眼、27%的低剂量治疗眼和0%的假性治疗眼在注射部位出现进行性萎缩。观察结束时，房颤萎缩面积的平均值（±SD）分别为 1.19 ± 1.75 mm2、0.25 ± 0.50 mm2 和 0.0 ± 0.0 mm2（假性×高剂量：P = 0.01）。与假性治疗的眼睛相比，高剂量治疗的眼睛在房颤（P = 0.01）和荧光血管造影（P = 0.02）中的萎缩病变明显更大。结论AAV.PDE6A 的视网膜下注射会在注射部位诱发剂量依赖性的进行性视网膜萎缩。多模态成像结果与视网膜和脉络膜内的局灶性、短暂性炎症以及继发性萎缩一致。使用基于AAV的载体系统进行基因治疗后出现的萎缩性变化主要不是由于手术创伤造成的，而且会随着注射剂量的增加而加重。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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