Eyevensys, SAS, 33 Avenue du Maine, 75015 Paris, France.
Eyevensys, SAS, 33 Avenue du Maine, 75015 Paris, France; Inserm UMR_S 1138, Team 17, Centre de Recherche des Cordeliers, Paris, France; AP-HP Hôpitaux de Paris, Ophtalmopole Hôpital Cochin, Paris, France; Sorbonne University, University of Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Paris Descartes University, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
J Control Release. 2018 Sep 10;285:244-251. doi: 10.1016/j.jconrel.2018.07.013. Epub 2018 Aug 1.
Non-infectious uveitis (NIU) is the first cause of blindness that can be cured if optimal anti-inflammatory therapy can be achieved. Systemic anti-TNF (Tumor Necrosis Factor) agents have been recently approved for NIU but no local delivery of anti-TNF is available. For sustained production of secreted therapeutic proteins into the eye, non-viral gene therapy using plasmid electrotransfer in the ciliary muscle has been proposed. In this paper, we report the development steps of pEYS606, a clinical-grade plasmid DNA, devoid of antiobiotic selection gene, encoding a fusion protein consisting of the extracellular domain of the soluble p55 TNF-α receptor linked to the human IgG1 Fc domain (hTNFR-Is/hIgG1 or Protein 6), with high affinity for human TNF-α, for non-viral gene transfer into the ocular ciliary muscle. Electrotransfer of pEYS606 in the ciliary muscle significantly reduced ocular inflammation in two well-established rat models of uveitis, the endotoxin-induced uveitis (EIU) and the experimental autoimmune uveitis (EAU). In addition, in EAU, a significant protection of photoreceptors was demonstrated after pEYS606 treatment. The improved pharmacokinetic profile of intraocularly-secreted protein as compared to direct intravitreous injection of recombinant protein allowed to demonstrate Protein 6 efficacy at very low concentrations. Based on these results, a phase I/II clinical trial is conducted [ClinicalTrials.gov Identifier: NCT03308045].
非感染性葡萄膜炎（NIU）是可治愈的致盲首要原因，如果能实现最佳抗炎治疗。最近已批准全身使用抗 TNF（肿瘤坏死因子）药物治疗 NIU，但尚无局部递送抗 TNF 的方法。为了持续将分泌型治疗蛋白递送至眼部，已经提出了使用睫状肌中的质粒电转染进行非病毒基因治疗。在本文中，我们报告了临床级质粒 DNA pEYS606 的开发步骤，该质粒不含抗生素选择基因，编码一种融合蛋白，该融合蛋白由可溶性 p55 TNF-α受体的细胞外结构域与人类 IgG1 Fc 结构域（hTNFR-Is/hIgG1 或蛋白 6）相连，对人 TNF-α具有高亲和力，用于非病毒基因转移到眼睫状肌中。pEYS606 在睫状肌中的电转明显减轻了两种已建立的葡萄膜炎大鼠模型（内毒素诱导的葡萄膜炎（EIU）和实验性自身免疫性葡萄膜炎（EAU））中的眼内炎症。此外，在 EAU 中，在用 pEYS606 治疗后，感光细胞得到了显著保护。与直接玻璃体内注射重组蛋白相比，眼内分泌的蛋白的药代动力学特征得到了改善，从而能够以非常低的浓度证明蛋白 6 的疗效。基于这些结果，正在进行 I/II 期临床试验[ClinicalTrials.gov Identifier：NCT03308045]。
